Salmonella spp. is one of the most common foodborne pathogens in humans. Here, we summarize the laboratory surveillance data of human non-typhoidal salmonellosis in Greece for 2003–2020. The total number of samples declined over the study period (p < 0.001). Of the 193 identified serotypes, S. Enteritidis was the most common (52.8%), followed by S. Typhimurium (11.5%), monophasic S. Typhimurium 1,4,[5],12:i:- (4.4%), S. Bovismorbificans (3.4%) and S. Oranienburg (2.4%). The isolation rate of S. Enteritidis declined (p < 0.001), followed by an increase of the less common serotypes. Monophasic S. Typhimurium has been among the five most frequently identified serotypes every year since it was first identified in 2007. Overall, Salmonella isolates were resistant to penicillins (11%); aminoglycosides (15%); tetracyclines (12%); miscellaneous agents (sulphonamides, trimethoprim, chloramphenicol and streptomycin) (12%) and third-generation cephalosporins (2%). No isolate was resistant to carbapenems. In total, 2070 isolates (24%) were resistant to one or two antimicrobial classes and 903 (10%) to three and more. Out of the 1166 isolates resistant to fluoroquinolones (13%), 845 (72%) were S. Enteritidis. S. Enteritidis was also the most frequently identified serotype with a resistance to third-generation cephalosporins (37%, 62/166), followed by S. Typhimurium (12%, 20/166). MDR was most frequently identified for S. Typhimurium and its monophasic variant (resistant phenotype of ampicillin, streptomycin, tetracycline and sulphamethoxazole with or without chloramphenicol or trimethoprim).