The archaeological site of Ancient Termez is located in southern Uzbekistan. Despite the arid environment, the city benefited from its strategic position near two rivers, the Amu Darya and the Surkhan Darya. Its significance was mainly related to the expansion of trade routes connecting Eurasia. The city comprises several enclosures that attest long-term human-environment interactions. In order to identify the adaptive dynamics of the settlement models during an extended chronology covering the period from c. 300 BCE to c. 1220 CE (Greco-Bactrian/Yuezhi, Kushan, Kushano-Sasanian, and Islamic periods), a multidisciplinary study has been carried out, which includes: (1) archaeological excavations in several areas of the urban complex; (2) pedestrian surveying inside some enclosures and in the urban periphery; (3) an aerial survey based on high-resolution satellite imagery; (4) AMS dating of charcoal and bone samples; (5) archaeobotanical investigation through anthracological analysis; (6) zooarchaeological studies. The results point to variations in the development of the inhabited spaces, in which abandonment and occupation took place. The zooarchaeological and archaeobotanical data demonstrate the exploitation of natural resources in different environments (i.e., arid areas and irrigated land) and a certain evolution during the period considered.