The rapid urban expansion and presence of volcanoes in the premises of Puebla River basin in central Mexico exert significant influences over its aquatic environments. Twenty surface sediment samples from Puebla River basin consisting of R. Alseseca, R. Atoyac, and Valsequillo dam were collected during September 2009 and analyzed for major (Al, Fe, Mg, Ba, Ca, and K) and trace elements (As, Cd, Co, Cr, Cu, Mn, Ni, Pb, Sr, V, and Zn) in order to identify the metal concentrations and their enrichment. R. Atoyac sediments presented higher concentrations of Ba (1193.8 μg g−1) and Pb (27.1 μg g−1) in comparison with the local reference sample values. All the metal concentrations except Sr for R. Alseseca sediments were within the range of local reference sample values indicating no significant external influence, whereas Valsequillo dam sediments had elevated concentrations of all the metals suggesting both natural and external influences in the study region. The magnitude of metal contamination was assessed using several indices such as geoaccumulation index (Igeo), enrichment factor (EF), degree of contamination (Cd), and pollution load index (PLI). The results suggest that As, Pb, and Zn were predominantly enriched in the Puebla River basin sediments. Comparing with sediment quality guidelines and ecotoxicological values, it is revealed that Cd, Cr, Cu, and Ni have possible harmful effects on the biological community. The present study provides an outlook of metal enrichment in Puebla River basin sediments, highlighting the necessity to conserve this river ecosystem for the near future.