The first Native Americans are thought to have arrived in Georgia during the period known by archaeologists as the Paleo-Indian period, extending from approximately 9,500 B.C. until 7,900 B.C. During this period, small bands of hunter-gatherers with Siberian origins pushed south and east from the Ice-Age glaciers covering much of Canada, finally arriving in the Ridge and Valley region of northwestern Georgia and surrounding states. Although comparatively little direct evidence has yet been documented in Northwest Georgia for the first culture documented for North America, called Clovis, spearpoints characteristic of this period have been found in other parts of the Ridge and Valley and surrounding regions, indicating that at least some Clovis groups were present in Northwest Georgia prior to 9,000 B.C. Similarly, later spearpoints called Cumberland are documented for Northwest Georgia, indicating continued presence through 8,500 B.C. During this time period, the Tennessee River valley is thought to have been a major "staging-ground" for immigrant Paleo-Indian groups to begin their expansion into marginal environmental zones, although the Coosa River basin has also produced evidence for occupation. Late Paleo-Indian points called Dalton (and related types called Quad and Beaver Lake) are comparatively more common than all earlier point types across the state between 8,500 and 7,900 B.C, although once again there is limited data specifically from Northwest Georgia. The Dalton period marked the end of the Ice Age, and thus prefaced increasingly modern environmental conditions for Georgia, including the final extinction of giant Pleistocene megafauna such as mastodon, mammoth, and bison.

Ample evidence has been found for subsequent occupation in Northwest Georgia during the Early Archaic period, dating to between 7,900 and 6,000 B.C. Relatively numerous side-notched and corner-notched spearpoints of the Big Sandy, Kirk, and Palmer varieties have been found in the region, as well as later and less-common points with bi-lobed bases, including LeCroy and St. Albans types. This period was also characterized by unifacially-flaked stone tools such as scrapers and awls, generally predating 6,000 B.C. These and other finds confirm that populations were expanding on the Georgia landscape during this initial post-Ice Age period. Early Archaic bands are thought to have moved seasonally within larger river drainages, practicing a yearly round that permitted them to exploit a diversity of resources in different habitats. Given the fact that Northwest Georgia is drained by several large rivers within two broader watersheds (the Tennessee and Coosa basins), the territorial ranges of several Early Archaic bands might have fallen within this region.

The Middle Archaic period (6,000-3,000 B.C) evidently witnessed further population growth in Northwest Georgia, as evidenced by the presence of a wide range of diagnostic spearpoints such as Stanley, Kirk Stemmed, Kirk Serrated, Morrow Mountain, Guilford, Benton, and Halifax. During this period, which coincided with a broad regional period of increased temperature and drier conditions called the Hypisthermal, the territorial ranges of growing numbers of Middle Archaic bands may have been increasingly limited across the region, prompting a generalized foraging lifestyle that resulted in the utilization of a wide range of habitats and landforms. Alternatively, there is evidence from other areas of the Tennessee River valley to indicate that some Middle Archaic groups evolved more sedentary lifestyles along riverine corridors with ample shellfish, suggesting increasing cultural diversity among regions.

The Late Archaic period, lasting from 3,000 B.C. until 1,000 B.C., was characterized by even more dense occupation in this and other regions of Georgia and the Southeast. Very large numbers of large and small stemmed spearpoints, including the large Savannah River and many other smaller varieties such as Otarre and Gary, have been found across Northwest Georgia, confirming not only population growth but considerably extensive use of a variety of habitats in lowland and upland zones. The initial appearance of both fiber-tempered pottery and steatite (or soapstone) bowl fragments in Northwest Georgia furthermore marks the spread of this new direct-heat cooking technology from other regions to the east and north after about 1,500 B.C. Grooved axes made from ground stone also appear during this period, providing the first indirect evidence for tree-felling as populations grew and supplies of wood for fuel and housing became limited.

The Woodland period, beginning after 1,000 B.C., marked the beginning of a number of culture changes, eventually to include increasingly sedentary lifestyles, the development of early horticulture, and the emergence of more complex forms of social organization and ceremonialism, including the appearance of rock and earthen mounds for burial or ritual purposes. From an archaeological standpoint, the Woodland period was marked by the rise of pottery technology, including the eventual appearance of several types decorated with impressions from fabric-wrapped wooden paddles, including the sand-tempered Dunlap Fabric Marked and limestone-tempered Long Branch Fabric Marked. These pottery types appear during the Kellogg phase, lasting from roughly 800 B.C. until roughly 100 B.C., and evidently marked by the emergence of formal village life along the river bottoms of Northwest Georgia. Sites of this period are often characterized by thick deposits of dark soil filled with village debris, and subsurface storage pits that apparently contained large volumes of acorns and hickory nuts. Spearpoints characteristic of this period include small stemmed varieties such as Coosa and Flint Creek, but these types were rapidly replaced by large triangular spearpoints such as Badin, Nolichucky, Copena, McFarland, and Yadkin, many of which lasted into the Middle Woodland Cartersville period.

The appearance and eventual predominance of Cartersville Check Stamped and Cartersville Simple Stamped pottery types corresponds to the replacement of the Kellog culture by the Cartersville culture after about 200 B.C. This culture was perhaps most notably characterized in Northwest Georgia by the eventual involvement of local populations in a broader cultural phenomenon called Hopewell, the influences of which were spread across much of eastern North America between about A.D. 200 and 500. The Hopewell culture was characterized by elaborate ceremonialism, particularly in association with mortuary ritual, and included an impressive array of elaborate artifacts crafted from exotic materials such as copper and obsidian obtained through long-distance trade. Although earthen burial mounds, animal effigy mounds, and earthen enclosures were characteristic of cultures in the Hopewell "heartland" to the north, local Georgia cultures used both rock and earth in mound construction, as was the case with the important Tunacunnhee site along Lookout Creek in Dade County, Georgia.

After A.D. 500, the Cartersville culture was replaced by the Late Woodland Swift Creek culture in Northwest Georgia, roughly coinciding with a decline in long-distance trade and ceremonialism characteristic of the Hopewell network. This culture was marked by the local appearance of the elaborately-decorated Swift Creek Complicated Stamped pottery (which had been in use for several centuries to the south), and a later though related type called Napier Complicated Stamped. Decorative designs, crafted using carved wooden paddles pressed into the wet clay, were frequently complex motifs combining abstract shapes with images from nature. Other artifacts characteristic of this culture include Bradley Spike and Jacks Reef Corner Notched projectile points, as well as a range of increasingly-smaller triangular points.

Toward the very end of the Woodland period the bow and arrow seems to have made its first appearance as a major technological innovation for hunting and warfare. After this time, tiny triangular arrowpoints (often called "bird points" among collectors) became common, replacing all earlier spearpoint types. In Northwest Georgia, this invention roughly coincided with the appearance of the Woodstock culture (ca. A.D. 750-1000), which straddled the boundary between the Late Woodland and Early Mississippi periods. Apart from the appearance of Woodstock Complicated Stamped pottery (evolving directly out of designs present in earlier Napier pottery), this intriguing culture also seems to have witnessed the beginnings of military fortifications such as stockades, palisades, and defensive ditches. This evidence, coinciding with the appearance of the bow and arrow, suggests that the Woodstock culture was characterized by comparatively extensive inter-group warfare, prefacing later developments during the Mississippi period.

The succeeding and last prehistoric culture period, the Mississippi period (A.D. 900-1540), was marked by the appearance of a new culture known as Etowah, and with it the emergence of powerful agricultural societies known as chiefdoms, which would dominate the Southeastern landscape over the next centuries. The Etowah culture (A.D. 1000-1200) was characterized archaeologically by the appearance of new nested-diamond and other designs called Etowah Complicated Stamped pottery, new pottery types tempered with crushed shell (instead of just sand and grit), and a range of other minority types such as red filmed and cordmarked. The Etowah culture would eventually spread from its origin in Northwest Georgia across much of the northern half of Georgia and beyond. The spread of the Etowah culture during these initial centuries coincided with the rise of similar chiefdoms in river valleys across the state, all generally characterized by hereditary leadership by a single family lineage over several thousand people distributed in villages, hamlets, and farmsteads along the arable bottomland soils of river and creek floodplains. Mississippian chiefdoms were also characterized by relative degrees of intensive agriculture, focusing on the cultivation of corn, beans, and squash. Chiefs maintained control by amassing considerable stores of surplus foodstuffs through the appropriation of human labor under their direction. This tributary labor and food was additionally directed toward public functions ranging from the construction of multi-stage earthen platform mounds to the maintenance of warriors for military action.

The widespread Etowah culture eventually evolved into the subsequent Savannah culture (A.D. 1200-1350), characterized by Savannah Complicated Stamped pottery with curvilinear designs such as nested circles, along with Savannah Check Stamped, and other types including shell tempered and red filmed varieties. During this time the Etowah Mounds site along the Etowah River near Cartersville was at its peak, and probably occupied a position of regional importance in Northwest Georgia. Other chiefdoms also existed in this region during the Mississippi period, probably remaining subordinate or tributary to Etowah until its apparent decline after the Savannah period. In addition to the Etowah chiefdom, other Northwest Georgia chiefdoms included clusters of village and mound sites along the Coosawattee River where it enters the eastern edge of the Ridge and Valley province, probably a comparable cluster in a similar position along the Conasauga River to the north along the Tennessee border, and a final cluster to the west along the Coosa River just downstream from Rome. Even though all four of these local chiefdoms undoubtedly interacted with one another, and were occasionally linked into broader multi-regional alliances, each riverine site cluster was normally surrounded by buffer zones with no year-round habitation.

Around A.D. 1350 a new culture known as Lamar emerged across most of northern Georgia and surrounding areas, marked by the appearance of new ceramic types such as Lamar Complicated Stamped and Lamar Incised, as well as Dallas and other shell tempered types related to contemporaneous cultures in Tennessee. By this time, the powerful chiefdom centered along the Etowah River had waned in regional importance, and archaeological and historical evidence suggests that its regional successor was the Coosawattee River chiefdom centered at Carters Lake in Murray County. The capital town of this chiefdom, known as Coosa, was described by the members of two separate Spanish expeditions during the 16th century.

During the summer of 1540, the army of Spanish explorer Hernando de Soto pushed south from Tennessee on their way into northeastern Alabama, visiting the capital town of Coosa (now located under Carters Lake Reregulation Reservoir) before marching on to the town of Itaba (Etowah) near Cartersville, and then turning west along the Etowah River to the town of Ulibahali, originally located in downtown Rome under the Coosa Country Club. Twenty years later, soldiers under the command of another Spaniard, Tristán de Luna, made their way upriver from southern Alabama in search of food in the famed Coosa chiefdom, passing again through Ulibahali before proceeding upriver to the Coosawattee River valley towns under the leadership of Coosa. And finally, in the fall of 1567, another Spanish expedition under Juan Pardo penetrated as far inland from the South Carolina coast as eastern Tennessee along the same route as Soto’s army, turning back shortly before arriving at Coosa.

Archaeological evidence confirms that in the aftermath of these Spanish expeditions, most or all of the Northwest Georgia chiefdoms collapsed within only a few decades as a result of rapid population loss due to European epidemic diseases such as smallpox and bubonic plague. Survivors from Coosa and its neighbors to the south and west apparently immigrated downriver into Alabama by 1600, leaving virtually all of Northwest Georgia abandoned for more than a century. Only the upper Conasauga River appears to have survived this period, since the remnants of the Conasauga River chiefdom known as Tasquiqui only reappeared under the name Tuskegee at the end of the 17th century among the Lower Creeks as fugitives from Cherokee expansion and English-sponsored slaving.

After the final abandonment of Northwest Georgia by the dwindling remnants of its native Muskogee-speaking populations by about 1700, immigrant Cherokees from the Blue Ridge began to repopulate the region by as early as 1715, when a town called Coosawattee was located at the old site of the Coosa capital at Carters Lake. In 1751, a fugitive South Carolina Cherokee town called Ustanali settled downriver along the Coosawattee, and after the 1776 destruction of the Cherokee Lower Towns in upper South Carolina and Northeast Georgia, a flood of Cherokee refugees spread out across the abandoned river and stream valleys of Northwest Georgia, along with the Chickamauga band of Cherokees under the separatist chief Dragging Canoe. In the aftermath of the American Revolution, the once-abandoned valleys of Northwest Georgia became home to substantial numbers of Cherokee farmsteads and towns, eventually forming the heart of the Cherokee nation with capitals at Ustanali and later New Echota along the Coosawattee River. By the time of removal in the 1830s, Northwest Georgia housed a substantial portion of the nearly 9,000 Cherokees living in the northern part of the state. Only after the creation of original Cherokee County and its many daughter counties, and the forced removal of all remaining Cherokees in the fall of 1838, did Northwest Georgia’s resettlement by Euro-American settlers replace the nearly 114 centuries of Native American occupation in this region.