In the context of climate change, precipitation and runoff in the arid inland basins of northwest China have undergone significant changes. The Qaidam Basin (QB) is a typical highland arid inland area. Understanding the spatial and temporal variations in surface water and groundwater chemistry and isotopes, as well as their causes, is crucial for future water resource management and ecological protection. Samples of river, lake, and groundwater, as well as others, were collected and tested in five typical watersheds in the summer and winter. The hydrochemistry and isotopic spatiotemporal differences in various water bodies were studied using the significant difference method, water vapor flux models, hydrochemistry, isotopes, and other methods for cause analyses. The results indicate the following: (1) There are differences in hydrochemistry between the southern and northern basins because the southern basin is more influenced by the dissolution of salt rocks and evaporation, whereas the northern basin is mainly affected by carbonate weathering. (2) The enrichment of δD and δ18O in the northern basin gradually increases from west to east, while in the southern basin, it is the opposite. This is because the southern basin receives a larger contribution of water vapor from the mid-latitude westerlies, while the northern basin primarily relies on local evaporation as its water vapor source. (3) Significant differences are observed in the total dissolved solids (TDS) and hydrochemical types of river water and groundwater between the summer and winter due to higher rates of rock weathering and evaporation in the summer. (4) The more pronounced seasonal differences in hydrogen and oxygen stable isotopes in the southern basin are due to higher rates of internal water vapor circulation in the summer. (5) The similarity in characteristics between river water and groundwater is the result of strong exchanges between river water and groundwater from piedmonts to terminals. The spatiotemporal heterogeneity of terminal lakes is attributed to the accumulation of salts and groundwater replenishment from other sources.