Objective To study the epidemiological characteristics and drug sensitivity of Salmonella in Huadu District of Guangzhou from January 2016 to December 2020, so as to provide scientific basis for prevention, control, diagnosis and treatment of diseases caused by this kind of pathogens. Methods Six thousand six hundred and sixty-five fecal samples of diarrhea patients in Huadu District of Guangzhou city from 2016 to 2020 were collected for isolation, identification, serotyping and drug sensitivity test. Results A total of 435 Salmonella strains were detected, with a total detection rate of 6.53%. The infection population was mainly infants (0-3 years old), and the sex ratio was male∶female=1.18∶1, which was not statistically significant. The epidemic peak was from May to November. General pediatrics, emergency medicine and gastroenterology were the three clinical departments with the highest positive detection rate. Salmonella typhimurium and Salmonella dublin were the dominant strains in the epidemic. Drug sensitivity test showed that the resistance rates of Salmonella to ampicillin, tetracycline, piperacillin and ampicillin/sulbactam were very high. The drug resistance rate of cephalosporins ranged from 17.01% to 22.63%. The resistance rate of quinolones (levofloxacin and ciprofloxacin) increased slightly. The result showed that the dominant strain of Salmonella in this area, Salmonella typhimurium, was less sensitive to β-lactam antibiotics in this study. Conclusion In the recent 5 years, Salmonella infection in Huadu District of Guangzhou city was on the rise, especially in infants. The drug resistance of Salmonella in this area was relatively strong, especially Salmonella typhimurium. It suggested that the monitoring of the epidemic should be strengthened in this area, and antibiotics be used reasonably in the treatment.