To study the distribution, sources and enrichment factors of groundwater As in the Shihezi area in Xinjiang, China, 19 indexes in 23 groundwater samples were tested and analyzed with a control area of 1611 km2. Results showed that As concentrations ranged between non-detected and 49.1 μg/L with an average of 11.0 μg/L. Among all the samples, 34.8% of which had As concentrations greater than 10 μg/L, according to “Standards for Drinking Water Quality (GB5749-2006)”. Groundwater As showed a significant spatial distribution. High-As groundwaters (>10 μg/L) were mainly distributed in the confined groundwater in the northern part of the study area. Arsenic concentrations in the deep confined groundwater were higher than that in the shallow confined groundwater due to mixed exploitation of groundwater in confined groundwater region and overexploitation of deep groundwater in the Shihezi area. The hydrogeochemical type of groundwater changed from HCO3·SO4–Ca·Na in the southern piedmont zone to HCO3·SO4–Na in the northern fine soil plain. High-As groundwater generally occurred under weakly alkaline and reducing conditions with dominant hydrogeochemical type of groundwater of HCO3·SO4–Na. Groundwater As mainly derived from As-containing minerals in the coal seam of the southern mountain and the extensive use of As-containing pesticides in agricultural areas. Enrichment of groundwater As was mainly influenced by climate, geological settings and hydrogeochemical characteristic. In the transition zone of oasis and desert in the north of study area, intensive evaporation of groundwater promoted the enrichment of As in shallow groundwater. In the confined groundwater area in the northern part of the study area, relatively weak groundwater runoff and reducing environment may contribute to groundwater As enrichment in confined aquifers. In addition, high pH values and high F− concentrations in the groundwater may contribute to the enrichment of groundwater As, while TDS, total Fe and Mn concentrations of groundwater had little effect on As enrichment in the study area. Two confined groundwater flow paths were selected in the study area. Inverse geochemical modeling was performed using PHREEQC. The results showed that As-containing realgar dissolved in groundwater, indicating that realgar was the major mineral source of groundwater As. The dissolved amount of realgar along deep confined groundwater flow path was higher than that along shallow confined groundwater flow path, indicating that the concentrations of As dissolved in deep confined groundwater were higher than that in shallow confined groundwater. Meanwhile, dissolution of fluorite in groundwater caused the increase in groundwater F−, which further confirmed that groundwater As and F− had a positive correlation.