Background/Objectives: AmpC enzymes, encoded by the blaCMY-2 gene, confer resistance to a broad range of β-lactam antibiotics, including first-, second-, and third-generation cephalosporins, as well as β-lactam/β-lactamase inhibitor combinations. These genes can be located either on the chromosome or plasmids, with the plasmid-borne form posing a greater risk due to its potential for rapid dissemination via horizontal gene transfer. The pESM megaplasmid, identified in Salmonella Minnesota isolates, was characterized as carrying the blaCMY-2 gene, underscoring the urgent need for surveillance and control measures to address the threat of widespread resistance. Methods: In this in silico study, we analyzed the frequency and geographic distribution of pESM among publicly available S. Minnesota genomes over the last 20 years. Results: A total of 935 sequences were identified, of which 648 (69.3%) carried pESM. The countries with the highest number of positive isolates were Saudi Arabia (n = 303) and Brazil (n = 155), with a predominance of samples derived from poultry (n = 423; 65.27%). Genes involved in yersiniabactin synthesis and transport (ybtT, ybtU, ybtS, and ybtX) exhibited high proportion within the pESM-positive genomes, as did the merA gene, which is associated with mercury tolerance. Multi-locus sequence type (MLST) analysis showed that only ST548 and ST9594 carried the pESM. Forty distinct plasmid incompatibility groups were identified, with the most frequent being IncA/C2 (79.79%), followed by Col440I (74.97%), IncR (9.95%), IncI-1 (6.74%), ColpVC (8.02%), ColRNAI (5.45%), IncQ1 (4.71%), and IncFII(S) (4.28%. All pESM-positive genomes carried blaCMY-2, with high co-occurrence of sul2, tet(A), and the mer operon, indicating that putative pESM could mediate resistance to multiple antibiotics and heavy metals. Since 2015, the co-occurrence of these genes with pESM has increased, likely reflecting selection pressure and clonal expansion of successful lineages. Phylogenetic analysis revealed a recent clade primarily composed of poultry-derived isolates from Brazil and Saudi Arabia. Putative pESM is strongly associated with the IncA/C2 incompatibility group and the qnrB19 gene, reinforcing its role in disseminating antimicrobial resistance. Conclusions: These findings suggest putative pESM is central in spreading multidrug resistance and virulence traits in S. Minnesota, especially in poultry environments. The plasmid’s prevalence in distinct sequence types and countries underscores its potential for horizontal transfer and global dissemination. Our results emphasize the need for enhanced surveillance of megaplasmids in foodborne pathogens and strategies to mitigate their spread.