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Nontyphoidal salmonellosis (NTS) is the second most commonly reported gastrointestinal infection in humans and an important cause of food-borne outbreaks in Europe. The use of antimicrobial agents for animals, plants, and food production contributes to the development of antibiotic-resistant <i>Salmonella</i> strains that are transmissible to humans through food. The aim of this study was to investigate the presence and the potential dissemination of multidrug-resistant (MDR) <i>Salmonella</i> strains isolated in the Marche Region (Central Italy) via the food chain. Strains were isolated from different sources: food, human, food animal/livestock, and the food-processing environment. Among them, we selected MDR strains to perform their further characterization in terms of resistance to tetracycline agent, carriage of <i>tet</i> genes, and plasmid profiles. Tetracycline resistance genes were detected by PCR and plasmid replicons by PCR-based replicon typing (PBRT). A total of 102 MDR <i>Salmonella</i> strains were selected among the most prevalent serovars: <i>S</i>. Infantis (n = 36/102), <i>S</i>. Derby (n = 20/102), <i>S</i>. Typhimurium (n = 18/102), and a monophasic variant of <i>S</i>. Typhimurium (MVST, n = 28/102). Resistance to sulfisoxazole (86%) and tetracycline (81%) were the most common, followed by ampicillin (76%). FIIS was the most predominant replicon (17%), followed by FII (11%) and FIB (11%) belonging to the IncF incompatibility group. Concerning the characterization of <i>tet</i> genes, <i>tet</i>B was the most frequently detected (27/89), followed by <i>tet</i>A (10/89), <i>tet</i>G (5/89), and <i>tet</i>M (1/89). This study showed the potential risk associated with the MDR <i>Salmonella</i> strains circulating along the food chain. Hence, epidemiological surveillance supported by molecular typing could be a very useful tool to prevent transmission of resistant <i>Salmonella</i> from food to humans, in line with the One Health approach.