Salmonella enterica non-typhoidal is a major contributor to diarrheal diseases, with over 2600 serovars identified across diverse environments. In Mexico, serovars Newport and Anatum have shown a marked increase, especially in foodborne disease, posing a public health problem. We conducted a cross-sectional study from 2021 to 2023 using active epidemiological surveillance to assess contamination in ground beef and pork at butcher shops nationwide. It involved isolation, phenotypic antimicrobial resistance, comparative genomics, spatial distribution, antimicrobial-resistance genes, and pangenome analysis. A total of 402 non-typhoidal S. enterica strains were isolated, including 59 Newport and 50 Anatum. After curating for redundancy, 45 Newport and 32 Anatum strains remained. We found that 75% of Newport strains exhibited multidrug resistance (MDR), compared to 25% of Anatum strains. Salmonella Newport also showed a broader distribution and stronger antibiotic-resistance capacity, particularly due to genes such as mphA and ramA. Our pangenome analysis showed a predominance of cell maintenance and survival-process genes in the accessory genome of both serotypes. Considering unique genes, Salmonella Anatum and Newport showed a notorious abundance of genes with functions related to replication, recombination, and repair. The substantial rise of Anatum and Newport strains in meat samples for human consumption presents an epidemiological alert, highlighting the critical need for stringent surveillance programs to mitigate human and ecosystem health risks.