Groundwater quality in the Muling–Xingkai Plain (MXP) is closely related to food security and human health. The chemical composition of groundwater in MXP has attracted great attention. A total of 168 groundwater samples were collected in MXP, and principal component analysis, chemical ion analysis and stable isotopic analysis were used to explore key factors affecting the chemical composition and hydrochemical evolution process of groundwater. Results show sources of chemical ions in groundwater are silicate minerals, carbonate minerals and domestic sewage. Domestic sewage is responsible for groundwater with high levels of Cl⁻, SO₄²⁻ and NO₃⁻, but a reduction environment can lead to groundwater with a high level of NH₄⁺ due to nitrification. Human activity and soil media together influence groundwater chemical composition. Groundwater with a high level of chemical ions is mainly collected from wells near river channels, where coarse-textured soils are overlying aquifers. The black soil far away from river channels can retard the infiltration of wastewater. Agricultural activities do not directly lead to deterioration of groundwater qualities, and agricultural non-point-source pollution does not occur in MXP. Nearly 70% of the population in MXP is living in the southern plain, where the influence of sewage on groundwater chemical composition is obvious. Thus, shallow groundwater far away from river channels is the best choice for irrigation. Some measures should be implemented to control the discharge of domestic sewage for the protection of groundwater. In addition, it is necessary to avoid the transformation of the redox environment of groundwater in the northern plain.