Evaporation is the key to the basin’s water cycle. Agricultural irrigation has resulted in a significant variation of regional potential evaporation (E_pen). The spatiotemporal variation of E_pen and the influencing factors in the natural, agricultural, and desert areas in different developmental stages of irrigation in the Heihe River Basin (HRB) from 1970 to 2017 are comparatively analyzed in this study. This work focused on the correction effect of irrigation on the variation of E_pen. The agricultural water consumption in HRB significantly varied around 1998 due to the agricultural development and water policy. Under the influence of irrigation, the annual variation of E_pen in the agricultural, natural, and desert areas was significantly different. From 1970 to 1998, the annual trend slope of E_pen in the natural area only reduced by 1 mm decade^-1, while that in the agricultural area significantly decreased by 39 mm decade^-1. After the implementation of water-saving irrigation, the E_pen in the natural and agricultural areas increased by 11 and 54 mm decade^-1, respectively, from 1998 to 2017. In contrast with the natural and agricultural areas, E_pen in the desert area decreased by 80 mm decade^-1 from 1970 to 1998 and continuously decreased by 41 mm decade^-1 from 1998 to 2017. However, the regulatory effect of irrigation on E_pen in the desert area started to manifest due to the expansion of the cultivated land area in the desert area from 2010 to 2017. Irrigation has a significant regulatory effect on the variation of E_pen in HRB. The regulatory effect is mainly reflected on the aerodynamic term (E_aero). The analytical results of the main meteorological factors affecting Epen in different regions indicated that the main meteorological factors influencing the variation of E_pen in each region are the wind speed 2 m above the surface (U₂) and the water vapor pressure difference (VPD).