In the past few decades, the shrinkage of the Aral Sea is one of the biggest ecological catastrophes caused by human activity. To quantify the joint impact of both human activities and climate change on groundwater, the spatiotemporal groundwater dynamic characteristics in the Amu Darya Delta of the Aral Sea from 1999 to 2017 were analyzed, using the groundwater level, climate conditions, remote sensing data, and irrigation information. Statistics analysis was adopted to analyze the trend of groundwater variation, including intensity, periodicity, spatial structure, while the Pearson correlation analysis and principal component analysis (PCA) were used to quantify the impact of climate change and human activities on the variabilities of the groundwater level. Results reveal that the local groundwater dynamic has varied considerably. From 1999 to 2002, the groundwater level dropped from −189 cm to −350 cm. Until 2017, the groundwater level rose back to −211 cm with fluctuation. Seasonally, the fluctuation period of groundwater level and irrigation water was similar, both were about 18 months. Spatially, the groundwater level kept stable within the irrigation area and bare land but fluctuated drastically around the irrigation area. The Pearson correlation analysis reveals that the dynamic of the groundwater level is closely related to irrigation activity within the irrigation area (Nukus: −0.583), while for the place adjacent to the Aral Sea, the groundwater level is closely related to the Large Aral Sea water level (Muynak: 0.355). The results of PCA showed that the cumulative contribution rate of the first three components exceeds 85%. The study reveals that human activities have a great impact on groundwater, effective management, and the development of water resources in arid areas is an essential prerequisite for ecological protection.