Climate change and geological shifts were pivotal in the survival and development of ancient human societies, especially in densely populated regions like the middle and lower Lishui River Basin. This study explored the dynamic interactions between ancient human cultures and the region’s natural environment, using field research alongside geological, geomorphological, and archaeological data spanning from the late Paleolithic to the Neolithic periods. Our findings showed that prehistoric sites in the middle and lower Lishui River Basin were primarily located in the low hilly areas surrounding the lower basin during the Paleolithic era, a pattern shaped by the region’s geomorphology. Early human settlements were strategically positioned near the Lishui River, offering access to vital resources while minimizing flood risk. These locations provided flat terrain, abundant vegetation, and materials for tool-making, factors that supported a hunting and gathering lifestyle. As the coldest phase of the last glacial period approached, the transition from the Paleolithic to the Neolithic eras marked a period of significant behavioral adaptation. In response to the harsher environment, humans began settling on lower terraces and miniaturizing their stone tools, signaling a shift to more specialized hunting techniques. This adaptability and resilience marked the refinement of hunting economies during this period. With the onset of the Holocene epoch and a warmer climate, conditions for human habitation became more favorable. Societies began migrating from the hills to the fertile lower Lishui River Basin, heralding the Neolithic period. This era saw the emergence of settlements and the onset of early rice cultivation, marking the transition from a hunting–gathering economy to one centered on agriculture. By the Daxi period, these settlements had expanded, extending their influence throughout the region. In conclusion, this study underscores the critical roles of climate change and geological features in shaping human settlement patterns, economic activities, and cultural evolution in the middle and lower Lishui River Basin. Our findings offer valuable insights into the evolutionary processes of ancient human cultures in the region and provide a foundation to understand future challenges in sustainable development.