The accurate inversion of actual evapotranspiration (ETa) at a regional scale is crucial for understanding water circulation, climate change, and drought monitoring. In this study, we produced a 1 km monthly ETa dataset for Turpan and Hami, two typical arid cities in northwest China, using multi-source remote sensing data, reanalysis information, and the ETMonitor model from 1980 to 2021. We analyzed the spatiotemporal variation of ETa using various statistical approaches and discussed the impact of climate and land use and cover changes (LUCC) on ETa. The results show the following: (1) the estimation results correlate well with ETa products on monthly scales (coefficient of determination (R2) > 0.85, root mean square error (RMSE) < 15 mm/month) with high reliability. (2) The ETa values were spatially distributed similarly to precipitation and LUCC, with the multi-year (1980–2021) average of 66.31 mm and a slightly fluctuating downward trend (−0.19 mm/a). (3) During the 42-year period, 63.16% of the study area exhibited an insignificant decrease in ETa, while 86.85% experienced pronounced fluctuations (coefficient of variation (CV) > 0.20), and 78.83% will show an upward trend in the future. (4) ETa was significantly positively correlated with precipitation (94.17%) and insignificantly positively correlated with temperature (55.81%). The impact of human activities showed an insignificant decreasing trend (85.41%). Additionally, the intensity of ETa varied considerably among land types, with the largest for cropland (424.12 mm/a). The results of the study have implications for promoting the rational allocation of regional water resources and improving water use efficiency in arid zones.