Spatiotemporal variations of ten physicochemical parameters in the water quality of Atoyac River basin, Central Mexico, were obtained from 22 sampling sites (66 samples in total) located all along the basin for three different seasons (dry, rainy and winter). Multivariate statistical techniques such as correlation matrix, factor analysis (FA) and cluster analysis (CA) were used as a tool to understand the process. Physicochemical parameters such as temperature (T), pH, conductivity (λ), dissolved oxygen (DO), spectral absorption coefficient (SAC), oxidation–reduction potential (ORP), turbidity, 5-day biochemical oxygen demand (BOD₅), chemical oxygen demand (COD) and total suspended solids (TSS) were analyzed. Extremely high values of pH (10.24), conductivity (1870 µS/cm) and reduced redox potential (−370.1 mV) were observed in the dry season, whereas elevated TSS of 2996 mg/L was detected during the rainy season. The results elucidated high influence from the adjoining industrial, agricultural and urban zones, making the river unsuitable for life. FA generated varifactors, which accounted for cumulative % of 75.04 (dry), 76.22 (rainy) and 79.96 (winter) clearly grouping the external factors responsible for these significant values indicating the source of contamination. Cluster analysis facilitated the ease of classifying the sampling sites based on the similarities of physicochemical parameters. This study carried out in different seasons using multivariate statistical techniques would definitely prove to be an efficient tool for the restoration and establishing the real-time monitoring stations along this important river basin of Mexico.