We describe the diet of Thamnophis melanogaster on the Mexican plateau, including geographic variation between populations in the Lerma and Tula drainages (represented by 39 localities), annual and seasonal variation in an isolated population in the Nazas drainage, and sexual and size-related variation in all three drainages. The Mexican Black-bellied Gartersnake inhabits banks of streams, rivers, canals, ponds, and lakes, where it captures fishes, leeches, crayfishes, tadpoles, earthworms, and frogs by foraging underwater. There was no geographic variation between the Lerma and Tula populations in proportions of prey taxa consumed, but whereas primary and secondary tadpole stages were consumed by snakes in Lerma, only secondary stages were consumed by snakes in Tula. Crayfishes, novel prey for this genus, were consumed over a restricted zone in the contiguous headwaters of the Lerma and Tula drainages. Interannual and seasonal variation in proportions of annelids and anurans ingested was documented in the Nazas population, and attributed to temporal change in relative abundance of prey taxa and snake size classes. Snake size was a major determinant of diet in all three drainages, affecting proportions of different prey taxa consumed and the upper limits on the mass of ingested prey. In the three drainages, sexes were similar in body size and consumed the same prey taxa in similar proportions and masses. We discuss proximate and functional determinants of diet and suggest that the observed interannual and seasonal variation observed in Mexican Black-bellied Snakes is due mostly to temporal variation in prey availability and proportions of snake size classes.