Elucidating the causes of the decline of many polities during the final centuries of the third millennium BCE remains one of the most important open questions in the archaeology of the Early Bronze Age (EBA) Near East. This phenomenon, which appears to have been particularly intense in northern Mesopotamia, has in recent decades been linked with a global climate fluctuation known as the 4.2 ka event. However, there is still disagreement among researchers regarding whether, and to what extent, this climatic shift was responsible for the widespread evidence of violence, site abandonment, and other disruptions which are characteristic of this period. Here, we employ stable carbon and oxygen isotope analysis on samples of human skeletal tissue to address this unresolved issue in the context of an EBA urban center in southeastern Anatolia known as Titriş Höyük. This city, which was the pre-eminent center in the Karababa Basin for centuries, was one of many sites that declined and were ultimately abandoned during the late third millennium. The results of our analysis suggest that the local climate did indeed become hotter and drier in the Late EBA, but also that this process did not result in the sudden abandonment of the site; instead, it appears that the process of decline at Titriş was gradual enough to leave traces in the isotopic record. Moreover, our data also show that the city’s residents were probably aware of their changing environmental circumstances and that they attempted to adapt through alterations in subsistence strategies.