Salmonella enterica subspecies enterica serovar Typhimurium (Salmonella Typhimurium) is considered a broad host range serovar, usually associated with gastroenteritis in a broad range of phylogenetically unrelated host species. The aim of this study was to compare the genetic diversity of core and accessory genes of a Salmonella Typhimurium population isolated from food-animal (pork, beef and chicken ) and human (with diarrhea, systemic infection and asymptomatic) sources in four regions of Mexico (from the Southeastern to the Northwestern part of Mexico). Multilocus sequence typing (MLST) and macrorestriction fingerprints by pulsed-field gel electrophoresis (PFGE) were used to address the core genetic variation. The presence of genes involved in antibiotic resistance carried in the Salmonella genome island (SGI1), integrons or the plasmid-borne betalactamase cmy-2 (pCMY-2), along with the Salmonella virulence plasmid (pSTV) were selected to evaluate the accessory genome. We found four multilocus genotypes, STs 19, 213, 302 and 429; ST19 was supported as the founder genotype. The most abundant genotypes, ST213 and ST19, were found in the four geographic regions and in almost all the sampled years. Interestingly, ST213 was more prevalent in food-animals than in humans, where ST 19 was predominant. We found a strong association between STs and antimicrobial resistance. ST213 strains presented higher percentages of resistance than ST19 strains, and all the strains resistant to ceftriaxone belonged to ST213. The resistance patterns varied across geographic locations. Yucatán was the state with the higher level of multidrug resistance, with an average of seven resistances per strain; while Sonora presented the lowest levels of resistance with an average of four. Furthermore, the ST213 ceftriaxone resistant strains displayed a differential geographic pattern, ranging from 100% of the ST213 strains in Yucatán to 0% in Sonora. We found strong associations among chromosomal genotypes and accessory genes. The general patterns of association can be summarized as follows: 1) the strains harbouring pSTV were ST19 or ST302; 2) all the strains with SGI1 were ST19 and most carried pSTV; 3) all the strains harbouring pCMY-2 were ST213; and 4) the abundant integron carrying dfrA12, orfF and aadA2 was present only in ST213 strains. The mapping of accessory genes and multilocus genotypes on the dendrogram derived from macrorestiction fingerprints allowed the establishment of genetic compartments within the population. The associations among chromosomal genotypes and accessory genes, suggests that this Mexican Salmonella Typhimurium population has been derived recently and has a clonal genetic structure, with low levels of genetic exchange among genetic compartments. It is noteworthy that ST213 did not harbor the pSTV virulence plasmid yet it could cause infection in humans.