Salmonella enterica serovar 1,4,[5],12:i:-(S. 1,4,[5],12:i:-) is an emerging pathogen that poses a significant risk of foodborne outbreaks, particularly through the contamination of animal-derived foods. This study aimed to investigate the antibiotic susceptibility and genetic diversity of 32 S. 1,4,[5],12:i:-isolates from animal-derived foods and humans in Shanghai, China. The results revealed a high prevalence of resistance among these isolates, particularly against ampicillin (71.9%), tetracycline (65.6%), tobramycin (53.1%), trimethoprim-sulfamethoxazole (40.6%), and ciprofloxacin (40.6%). Furthermore, more than half of the isolates (56.3%) exhibited multidrug resistance. Pulsed-field gel electrophoresis analysis revealed ten distinct PFGE patterns. Several pork and clinical isolates grouped into the same pattern with 100% genetic similarity, indicating sig-nificant transmission of S. 1,4,[5],12:i:-through pork. Additionally, nine plasmid incompatibility groups (Inc) were identified, with IncQ1, IncHI2A, and IncHI2 being the most prevalent types. Interestingly, 15 isolates from foods and humans contained both IncHI2A-HI2 plasmids. These plasmids carried numerous resistance genes (e. g., blaCTX-M, blaTEM, blaOXA), suggesting their potential role in the transfer of resistance genes. The findings un-derscore the high prevalence of MDR S. 1,4,[5],12:i:-isolates in animal-derived foods and humans. Strengthening surveillance of animal-derived food isolates is crucial to prevent and control their spread in the food chain.