Abstract Background Salmonella enterica is a leading cause of human gastroenteritis. S. enterica strains that produce ESBLs (ESBL-Salm) remain rare in Europe and North America, but less is known about their prevalence among animal-derived foods in countries with weaker food safety practices and unregulated veterinary antibiotic use. Objectives To examine the prevalence and characteristics of ESBL-Salm from retail meats in Phnom Penh, Cambodia. Methods We tested fish, pork and chicken from two markets for ESBL- and carbapenemase-producing Salmonella from September–December 2016, using cefotaxime- and ertapenem-supplemented media, respectively. ESBL-Salm were sequenced and their genomes characterized. We performed plasmid conjugation experiments to assess the co-transferability of ESBL-encoding genes and MDR phenotypes. Results Twenty-six of 150 fish and meat samples (17%) were positive for ESBL-Salm, including 10/60 fish (17%), 15/60 pork (25%) and 1/30 chicken (3%). Carbapenemase-producing Salmonella strains were not detected. Pork-origin ESBL-Salm were primarily serotypes Rissen (10/15) or a monophasic variant of Typhimurium 4,5,12:i:− (3/15), whereas Saintpaul (3/10) and Newport (4/10) were more common among fish. Most ESBL enzymes were encoded by blaCTX-M-55 genes (24/26) harboured on conjugative IncA/C2 (n = 14) or IncHI2 (n = 10) plasmids. Resistance to up to six additional drug classes was co-transferred by each plasmid type. ESBL-Salm were resistant to almost every antibiotic recommended for severe salmonellosis treatment. Conclusions CTX-M-55-type S. enterica are highly prevalent among pork and fish from Phnom Penh markets and their spread appears to be mediated by MDR IncA/C2 and IncHI2 plasmids. Food safety must be improved and veterinary antibiotic use should be regulated to protect public health.