The global dissemination of multidrug-resistant (MDR) Salmonella through the international food trade poses a major One Health concern. We used whole-genome sequencing to characterize Salmonella isolates from poultry meat sold in Chile, including domestic and imported products from Brazil and Argentina. Sixty-one Salmonella isolates were recovered from poultry meat; S. Infantis predominated (59%), followed by S. Heidelberg. Among S. Heidelberg from imported-meat poultry, 92% carried the bla_CMY-2 gene, conferring resistance to β-lactams. Given the predominance of S. Infantis in poultry meat, we performed an additional in-depth genomic analysis of 73 S. Infantis isolates obtained from poultry meat (n = 32), surface water (n = 30), and human clinical cases (n = 11). Across sources, phenotypic resistance to ciprofloxacin and third-generation cephalosporins reached 93% and 70%, respectively, and MDR (≥3 antimicrobial classes) occurred in 71% of isolates, largely associated with bla_CTX-M-65 and gyrA mutations. The pESI (plasmid of emerging S. Infantis)-like plasmid, harboring antimicrobial resistance and virulence genes, appeared in 94% of isolates. Phylogenetic analyses showed close genetic relationships among food, environmental, and clinical isolates, suggesting potential transmission through contaminated poultry meat or water. These findings emphasize the emergence of MDR S. Infantis in Chile and underscore the need for integrated One Health surveillance and prudent antimicrobial use to mitigate foodborne AMR risks.