Staphylococcus aureus is a major pathogen capable of causing foodborne diseases (FBDs) in fresh meat products and ready-to-eat (RTE) sandwiches. Therefore, investigating antimicrobial therapies that are safe and efficacious will benefit food safety. Zinc oxide nanoparticles (ZnO-NPs) were synthesized, characterized, and used to combat MDR S. aureus isolated from RTE meat sandwiches in this study. The incidence of S. aureus was determined to be 81.42% in the beef burger, 72.85% in the kofta, 68.57% in the sausage, and 58.57% in the hot dog. Mean coagulase-positive S. aureus (CPS) counts for a beef burger, kofta, sausage, and hot dog were 1.14104, 7.4103, 6.5103, and 4.9103 CFU/g, respectively. Eighty-eight of the isolates were MDR S. aureus with a MAR index ranging from 0.3 to 1.0. Out of 18 MDR S. aureus isolates, 77.7% expressed the presence of the blaZ gene. The presence of aacA-aphD, mecA, vanA, apmA, cfr, spc, and aadE genes was estimated by 66.6, 66.6, 61.1, 55.5, 44.4, 38.8 and 33.3%, respectively. In 18 MDR S. aureus isolates, see and sea were the virulence-spreading genes in 55.6%, sec and pvl in 50%, tst and clfA in 44.4%, sed and fnbA in 38.9%, fnbB in 33.3%, and seb in 22.2%. The ZnO-NPs demonstrated notable antibacterial efficacy against the examined MDR S. aureus isolates, with the mean values of the inhibition zones ranged from 9.96 +/- 0.5 to 27.12 +/- 0.3 mm. The MIC values varied between 12.5 and 25 mu g/mL. These findings suggest that ZnO-NPs have the potential to be developed as an antibacterial agent to control the growth of MDR S. aureus in RTE food.