The Karst aquifers are usually characterized by high spatial heterogeneity in the humid tropics and subtropics, evidenced by specific landforms features (e.g., heavily fractured outcrops, sinkholes, etc.) and complex subterranean conduit networks. The marked high heterogeneity leads to the temporal–spatial variability of hydrological and hydro-chemical processes, making its environments extremely vulnerable to natural and anthropogenic hazards. The complicated temporal–spatial variability of hydrochemistry in karst systems depends on several underlying factors which influence the hydro-chemical processes. Investigating the factors of the karst water hydrochemistry variability is necessary to understand the hydro-chemical processes and mitigate natural and anthropogenic hazards for ensuring the sustainability of karst water resources. In this paper, an attempt is made to couple geostatistical and geochemical analysis to extract the underlying controlling factors and effective information about the geochemical evolution behave of karst water in Houzhai karst area, southwestern China. Factor analysis was performed to obtain significant statistical relationship of the hydrochemistry variation in the Houzhai karst basin. The ordinary kriging method was applied to the factor scores to investigate the contributions of factors on different regions. The results of the factor analysis indicated four principal factors which explained > 81.678% of the total sample variance: (1) the dilution effect by rainfall; (2) the dissolution effect dominated by calcite; (3) the human agricultural activities effect; (4) the migration of dissolved components under the control of alkaline environments in karst water. It revealed that the dilution effect was more significant (36.579%) than the dissolution effect (22.036%) and human agricultural activities effect (14.596%). These factors made more significant difference of contributions on the karst area in the dry periods than in the rainy periods. The dilution process by rainfall and the dissolution process of carbonate rock had a great influence on the upstream area whereas the human agricultural activities played important roles in the middle-stream area, especially in the dry periods. This integrated approach which combine factor analysis with kriging method is effective in the identification and interpretation of factors related to the variability of hydrochemistry, as well as the contributions of these factors on space and time.