The spatio-temporal evolution of human subsistence strategies and their driving force in prehistoric Eurasia has received increasing attention with the rapid development of archaeobotanical, zooarchaeological, and isotopic research in recent decades, while studies focusing on the historical periods are relatively absent. In the Hexi Corridor in northwestern China, which has served as a hub for trans-Eurasian exchange since the late prehistoric period, archaeobotanical data have been reported from numerous Neolithic and Bronze Age sites, as well as sites from the Wei and Jin Dynasties (220–420 BCE) to the Yuan Dynasty (1271–1368 BCE). However, no archaeobotanical study has been conducted at sites of the Han Dynasty (202 BCE–220 CE), a crucial period connecting prehistoric and historical eras. In this study, we identified 32475 plant remains, including 31,463 broomcorn millets, 233 foxtail millets, and 780 weeds, from the Shuangdun North Beacon Tower (SDNBT) site of the Han Dynasty at the western end of the Hexi Corridor, suggesting that millets played a prominent part in human subsistence strategies in the area during this period. In addition, sheep, chicken, dog, horse, and rodent remains were also collected at the site. By applying a multi-disciplinary approach, we detected a remarkable change in plant-based subsistence in the ancient Hexi Corridor. Specifically, the importance of millet crops, compared with other crops (especially barley and wheat), in plant-based subsistence declined from the Late Neolithic to the Bronze Age; it apparently improved during the Han and Sui-Tang Dynasties (581–907 CE), when agricultural empires controlled the area, and then declined again during the Wei, Jin, Northern, and Southern Dynasties (220–581 CE) and the Song-Yuan Dynasty (960–1368 CE), when nomadic regimes controlled the area. Climate change, trans-Eurasian exchanges, and geopolitical shifts influenced the diachronic change in plant-based subsistence from the Late Neolithic to the historical periods in the Hexi Corridor.