Objective: To analyze the whole genome characteristics of Salmonella in diarrhea cases in Hohhot City, so as to provide the evidence for the prevention and control of Salmonella infection and rational clinical use of antibiotics. Methods: Salmonella strains were isolated and identified from fecal specimens of acute diarrhea cases at sentinel hospitals for national foodborne disease surveillance in Hohhot City from 2021 to 2023. DNA was extracted for whole genome sequencing. Bioinformatics analysis based on the Microobench Pathogen Genome Analysis System was conducted to determine serotypes, multi-locus sequence typing (MLST), drug resistance genes, and virulence genes. Additionally, 60 Salmonella genomic sequences from different regions across China were downloaded from the NCBI Genome database. A phylogenetic tree was constructed based on core-genome MLST (cgMLST) to analyze the phylogenetic relationship between strains from Hohhot City and those from other regions of China. Results: From 2021 to 2023, a total of 42 Salmonella strains isolated in Hohhot City were classified into 12 serotypes. Salmonella Enteritidis ST11, Salmonella I 4,[5],12:i:- ST34, and Salmonella Typhimurium ST19 were identified as the dominant strains, represented by 13, 10, and 6 isolates, which accounted for 30.95%, 23.81%, and 14.29%, respectively. Seventy-seven drug resistance genes belonging to 12 classes were detected. Among them, 17 Salmonella strains carried amino acid substitutions in the fluoroquinolone resistance-determining region caused by mutations at the gyrA and parC loci. Virulence genes covered all stages of Salmonella pathogenesis, with a predominance of genes associated with adhesion. Phylogenetic tree analysis results revealed that the 42 Salmonella strains from Hohhot City were distributed across evolutionary branches A, B, C, D, and F. They clustered with 60 strains from other regions of China, suggesting potential cross-regional transmission. Conclusions Salmonella strains isolated in Hohhot City exhibited diverse serotypes, carried multiple drug resistance genes and virulence genes, and displayed high genetic diversity. These findings indicate a potential risk of cross-regional transmission, highlighting the need for enhanced surveillance and prevention measures.