Land use change greatly affects groundwater hydrochemical cycling and thereby food and ecosystem security in arid regions. Spatiotemporal distribution of groundwater hydrochemistry is vital to understand groundwater water-salt migration processes in the context of land use change, while it is not well known in the oasis-desert region of arid inland basins. Here, to investigate the influences of land use change on groundwater hydrochemistry and suggest sustainable management, 67 water samples were obtained in the Luntai Oasis, a typical oasis desert of Central Asia. Stable isotopes and chemical components of samples were analyzed. Piper and Gibbs plots were used to elaborate the chemical type and major mechanisms controlling water chemistry, respectively. The results showed that cultivated land area has markedly expanded in the Luntai Oasis over the last 20 years (increasing by 121.8%). Groundwater seasonal dynamics and groundwater–surface water interaction were altered dramatically by farmland expansion and groundwater exploitation. Specifically, the spatial heterogeneity and seasonal variability of groundwater hydrochemistry were significant. Compared with the desert area, the δ18O and TDS of river water and shallow groundwater in the oasis cropland exhibited lower values but greater seasonal variation. Higher TDS was observed in autumn for river water, and in spring for shallow groundwater. The chemical evolution of phreatic water was mainly controlled by the evaporation-crystallization process and rock dominance, with a chemical type of Cl-SO4-Na-Mg. Significant spatiotemporal heterogeneity of groundwater hydrochemistry demonstrated the influence of climatic, hydrogeological, land use, and anthropogenic conditions. Groundwater overexploitation would cause phreatic water leakage into confined water, promoting groundwater quality deterioration due to fresh saltwater mixing. Improving agricultural drainage ditches in conjunction with restricting farmland expansion and groundwater extraction is an effective way to alleviate groundwater environment deterioration and maintain oasis-desert ecosystems in arid regions.