Salmonella is the most common cause of salmonellosis, a foodborne infection that is transmitted by consuming contaminated food. It is becoming more prevalent worldwide, particularly in Cambodia. Additionally, Salmonella is recognized as one of the drug-resistant bacteria, posing serious public health problems that spread quickly due to the misuse and overuse of antibiotics in healthcare, livestock husbandry, and agriculture. Therefore, the purpose of this study was to determine the occurrence of Salmonella from different food matrices in Cambodia and to assess its profile of antibiotic resistance, including the detection of extended-spectrum beta-lactamase (ESBL) resistant genes. From January to December 2023, a total of food samples (n=1,506), categorized into twenty-two sample types, were tested for Salmonella using the standard method ISO 6579-1:2017. The positive Salmonella were subjected to antimicrobial susceptibility testing by using disc diffusion method against 22 antibiotics following the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines.. The ESBL-producing Salmonella were screened for the resistance genes via conventional PCR. The results showed that Salmonella was present in 2.7% (40/1506) of the analyzed food samples originated from seafood (10.3%), fish and fish products (13.8%), and meat and meat products (28.7%). Antimicrobial susceptibility assay revealed that 57.5% (23/40) were resistant to amoxicillin, piperacillin, and ticarcillin, and 52.5% (21/40) were resistant to nalidixic acid, while 35% (14/40) of the Salmonella isolates were susceptible to all of the antibiotics tested. It was also found that 45% (18/40) of Salmonella isolates were multidrug-resistant (MDR) and 27.5% (11/40) were ESBL-producing strains originated from all samples of meat and meat products. Molecular detections revealed that 45.5% of the ESBL-producing Salmonella isolates carried bla CTX-M group 9 genes. Our findings demonstrated the primary sources of Salmonella contamination, including seafood, fish, and meat, and meat products serving as a significant reservoir for multidrug-resistant (MDR) and ESBL-producing strains. This pathogen's emergence highlights the need for regulatory measures intended to restrict the use of antibiotics in food agriculture.  As a recommendation, further study should employ other PCR primers to determine the remaining ESBL-producing strains in combination with sequencing to define the specific resistance genes, or whole genome sequencing, to comprehensively identify resistance genes and trace the spread of resistant Salmonella strains in the food production environment.