The Aksu River Basin is located in the western region of the middle part of the southern foothills of the Tianshan Mountains and the northwestern edge of the Tarim Basin in Xinjiang, China. High-arsenic (As)/high-fluoride (F) groundwater is widely distributed in this area and is harmful to the life of local residents and to agricultural production. It is of great importance to understand the distribution and causes of As-F co-enrichment in the groundwater in this area. Based on the test results of 138 groundwater samples in the plain area of the Aksu River Basin, the hydrochemical characteristics of groundwater and the spatial distribution of As-F co-enrichment groundwater were analyzed under the following conditions: a single-structure phreatic aquifer (SSPA), a phreatic aquifer in a confined groundwater area (PACGA), a shallow confined aquifer (SCA), and a deep confined aquifer (DCA), all in a recharge area, transition area, and an evaporation area. The hydrogeochemical processes affecting the source, migration, and enrichment of As-F in the groundwater were revealed. The results showed that the chemical types of groundwater in the study area were mainly HCO3·SO4-Ca·Mg and SO4·Cl-Na·Mg. Horizontally, high-As-F groundwater was mainly distributed in the transition area and evaporation area in the middle and lower reaches of the Aksu River Basin. The area is close to the edge of the desert, where the groundwater runoff is sluggish and in an alkaline-reducing groundwater environment. Vertically, high-As groundwater was mainly distributed in the PACGA at a depth of 10–20 m and in the SCA at a depth of 80–100 m. High-F groundwater was mainly concentrated in the PACGA at a depth of 10–30 m and in the SCA at a depth of 80–100 m, and As-F co-enrichment groundwater was mainly concentrated in the PACGA at a depth of 10–20 m and in the SCA at a depth of 80–100 m. The hydrochemical characteristics of the groundwater in the Aksu River Basin were closely related to geological conditions, hydrogeological conditions, and the hydrochemical environment of the groundwater. As-F co-enriched groundwater was mainly affected by the combination of a small topographic gradient, a shallow groundwater burial depth, a weak reducing alkaline groundwater environment, strong evaporation and concentration, the weathering and dissolution of evaporated salt rock, and the alternating adsorption of cations.