The long–term monitoring results have shown significant changes in the groundwater environment in the middle reaches of the Heihe River in Zhangye area since the 1980s. Time series analysis, correlation analysis and remote sensing interpretation were applied to analyze the evolution of groundwater level, groundwater hydrochemistry, mountain runoff of Heihe river, meteorological elements, and oasis area in this area in recent 40 years, and to identify the response of groundwater environment to climate change and human activities. The results demonstrate that groundwater level changes in the central part of the study area are significantly correlated with the runoff from the mountain, and poorly correlated with the precipitation in Zhangye area. Climate change affects the groundwater level in the central part of the study area by affecting the runoff in the upper reaches of Heihe river. Rainfall change in the study area has a weak impact on the groundwater level. The change of groundwater level in the west and east of the study area is significantly affected by human activities. Affected by the continuous increase of surplus water, the groundwater level in the eastern pre–mountain area has risen significantly in recent years, while the groundwater level in the well irrigation area from Minghua township to Camel City in the west is still in a state of continuous decline due to the massive exploitation of groundwater. The groundwater chemical characteristics in a certain range on both sides of the river in the southern pre–mountain area have remained stable for many years, while significant changes have been observed in other areas.