Indigenous populations of the Americas experienced high mortality rates during the early contact period as a result of infectious diseases, many of which were introduced by Europeans. Most of the pathogenic agents that caused these outbreaks remain unknown. Using a metagenomic tool called MALT to search for traces of ancient pathogen DNA, we were able to identify Salmonella enterica in individuals buried in an early contact era epidemic cemetery at Teposcolula-Yucundaa, Oaxaca in southern Mexico. This cemetery is linked to the 1545-1550 CE epidemic locally known as 'cocoliztli', the cause of which has been debated for over a century. Here we present two reconstructed ancient genomes for Salmonella enterica subsp. enterica serovar Paratyphi C, a bacterial cause of enteric fever. We propose that S. Paratyphi C contributed to the population decline during the 1545 cocoliztli outbreak in Mexico.