Abstract: Objective　To analyze the serotypes, drug resistance, and molecular epidemiological characteristics of non-typhoidal Salmonella in Chaozhou City, Guangdong Province in 2022, providing pathogenic support for the effective prevention and control of foodborne diseases. Methods In 2022, human-derived non-typhoidal Salmonella strains and food-derived strains were isolated through sentinel surveillance and food risk monitoring in Chaozhou City, Guangdong Province. The strains were subjected to serotyping, drug susceptibility testing, and whole-genome sequencing analysis. Results A total of 1 257 fecal specimens were collected for diarrhea surveillance in Chaozhou City in 2022, and 58 strains of non-typhoidal Salmonella were detected, with an isolation rate of 4.61%. Among 116 foodstuffs, 2 strains of non-typhoidal Salmonella were detected, with an isolation rate of 1.72%. Early childhood was the main age group for infection (14/144, 9.72%). The highest detection rate was in June (12/123, 9.76%). The 58 human-derived non-typhoidal Salmonella strains were classified into 12 serotypes, with Salmonella typhimurium being the most prevalent (44/58, 75.86%). In terms of drug resistance, 55 strains showed resistance, with a resistance rate of 91.67%, among which ampicillin, tetracycline, chloramphenicol, and streptomycin had the highest resistance rates, 76.67%, 70.00%, 67.67%, and 60.00%, respectively. Forty-nine strains were multi-resistant, accounting for 81.67%. From the molecular characteristics standpoint, multilocus sequence typing (MLST) divided the strains into 14 sequence typing (ST), with Salmonella typhimurium ST34 being the dominant type. Whole-genome single nucleotide polymorphism (wg-SNP) evolutionary analysis revealed high genetic heterogeneity among the studied strains, with Salmonella typhimurium clustering together and showing close evolutionary relationships to clinical samples of Salmonella enteritidis. Conclusions In 2022, the non-typhoidal Salmonella strains from Chaozhou showed a diversity of serotypes, with Salmonella typhimurium being predominant and exhibiting severe multidrug resistance. Molecular typing revealed diverse evolutionary characteristics.