Understanding groundwater geochemistry is crucial for water supply in arid regions. The present research was conducted in the arid Mo river watershed on the Tibetan plateau to gain insights into the geochemical characteristics, governing processes and quality of groundwater in arid endorheic watersheds. A total of 28 groundwater samples were collected from the phreatic and confined aquifers for hydrochemical analysis. The results showed that the groundwater was slightly alkaline in all aquifers of the watershed. The phreatic groundwater samples (PGs) and confined groundwater samples (CGs) had the TDS value in the ranges of 609.19–56,715.34 mg/L and 811.86–2509.51 mg/L, respectively. PGs were salter than CGs, especially in the lower reaches. Both the PGs and CGs were dominated by the Cl-Na type, followed by the mixed Cl-Mg·Ca type. The toxic elements of NO2− (0.00–0.20 mg/L for PGs and 0.00–0.60 mg/L for CGs), NH4+ (0.00–0.02 mg/L for PGs and 0.00–0.02 mg/L for CGs) and F− (0.00–4.00 mg/L for PGs and 1.00–1.60 mg/L for CGs) exceeded the permissible limits of the Chinese guidelines at some sporadic sites. Water–rock interactions, including silicates weathering, mineral dissolution (halite and sulfates) and ion exchange, were the main contributions to the groundwater chemistry of all aquifers. The geochemistry of PGs in the lower reach was also greatly influenced by evaporation. Agricultural sulfate fertilizer input was responsible for the nitrogen pollutants and salinity of PGs. All CGs and 73.91% of PGs were within the Entropy-weighted water quality index (EWQI) of below 100 and were suitable for direct drinking purposes. Precisely 8.70 and 17.39% of PGs were within the EWQI value in the range of 100–150 (medium quality and suitable for domestic usage) and beyond 200 (extremely poor quality and not suitable for domestic usage), respectively. The electrical conductivity, sodium adsorption ratio, sodium percentage and permeability index indicated that groundwater in most parts of the watershed was suitable for irrigation, and only a small portion might cause salinity, sodium or permeability hazards. Groundwater with poor quality was mainly distributed in the lower reaches. CGs and PGs in the middle-upper reaches could be considered as the primary water resources for water supply. Agricultural pollution should be paid more attention to safeguard the quality of groundwater.