The quality of drinking water is crucial for human health and the sustainable development of societies. The Aksu River Basin, a typical inland river system, has areas where groundwater arsenic levels exceed safe drinking water standards (i.e., arsenic concentrations greater than 10 μg/L). Identifying the causes of high arsenic levels in the basin’s groundwater requires further study. Analyzing the hydrogeochemical composition of the Aksu River basin helps us to understand the spatial distribution of groundwater environments and locate areas with dangerously high arsenic levels. In this research, we collected 196 groundwater samples from along the river. Out of these, 38 samples had arsenic levels above 10 μg/L, which represents 19.4% of the total samples collected. By examining the slope changes in the cumulative frequency curves of major ion ratios and employing geostatistics (specifically, the Kriging interpolation), and taking into account the environmental characteristics of the entire basin, we divided the study area into five sub-regions (Zone I through Zone V). The geostatistical analysis showed a significant spatial variability in groundwater arsenic levels, with a clear spatial correlation. Our findings demonstrate that arsenic concentrations in the Aksu River basin’s groundwater vary widely, with Zones II and III—mainly located in the northeastern part of the basin and in Awat County—being hotspots for high-arsenic water. Factors such as a weak reducing environment, intense evaporation, strong cation exchange, and the low-permeability recharge of surface water contribute to the accumulation of arsenic in the basin’s groundwater. The results of this study are vital for assessing the risk of arsenic contamination in groundwater in similar basins and for identifying critical areas for further investigation and research.