Potential evapotranspiration (PET) is a crucial variable for implementing adaptation measures to mitigate the potential impacts of climate change on water resources. In the context of global warming, PET is essential for predicting water resource supply and demand, guiding irrigation and water management decisions. However, there is limited understanding of the spatiotemporal changes in PET and its driving factors in the hyper-arid regions of Northwest China. In this study, the Hargreaves model was employed to estimate PET in the Hami region from 1991 to 2020. By combining relevant climate data and partial correlation analysis, we investigated the spatiotemporal distribution patterns of PET within the study area and analyzed the factors influencing these patterns. The results showed the following: (1) From 1991 to 2020, the overall PET in the Hami region demonstrated a tendency to rise. The interannual trend rates of PET for the full year, spring, summer, autumn, and winter were 0.933, 2.744, 0.906, 0.488, and −0.406 mm·a-1, respectively. Despite a decreasing trend in winter PET, the other seasonal PET values and the annual PET values exhibited an increasing trend. (2) The spatial distribution of both annual and seasonal PET showed significant regional heterogeneity, following a consistent pattern marked by lower values in the central part and higher values in the surrounding areas. The southern region tended to have relatively high PET, while the northwestern region experienced comparatively low PET. (3) Partial correlation analysis indicated significant differences in the impact of various climatic factors on PET. The maximum temperature emerged as the dominant factor influencing annual PET variation, while precipitation played a leading role in influencing autumn PET variation. This study underscores the influence of climate change on PET in the Hami region, contributing to an enhanced comprehension of PET variations.