Over the past decade, the rising prevalence of antibiotic resistance has posed a significant challenge to the effective treatment of numerous bacterial infections. Creating novel antimicrobial biomaterials, which unavoidably have expanded therapeutic possibilities in medical methods, also requires innovative nanomaterials. It prompts several attempts to develop novel metal oxide nanoparticles (NPs) to more effectively control the Multi Drug Resistant (MDR) bacteria responsible for diabetic foot ulcers. This work used the sol-gel method to produce zinc oxide nanoparticles, which were then characterized by X-ray diffraction, Fourier-transformed infrared, and transmission electron microscopy. The pure phase of non-agglomerated ZnO-NPs with diameters ranging from 30 to 50 nm and an average diameter of 40 nm was synthesized using the employed approach in conjunction with TEM analysis. The TEM examination indicates that the morphology of ZnO-NPs has developed to be nearly hexagonal. On the other hand, the infection by MDR S. aureus represented 21.3 % of the causes of staphylococcal diabetic foot ulcers. The treatment by ZnO-NPs inhibited the growth of Methicillin, heterogenous Oxacillin Resistant or Vancomycin Intermediated S. aureus (MRSA, ORSA, and VISA) phenotypes with an average MIC of 5.21 mM/ml. At the same time, they give MIC average values of 3.49, 2.6, 2.99, and 1.99 μg/ml for (OX, FOX, VA, and LN) individual antibiotics, respectively. In the same aspect, using syn-MICs of antibiotics and ZnO-NPs by (1:1) decreased values by a synergistic effect percentage of 309, 441, 299, and 316 %, respectively. This finding indicates a synergistic effect of combining ZnO-NPs and the tested antibiotics. This result suggests a synergistic interaction between ZnO-NPs and the tested antibiotics. According to the findings, ZnO-NPs are promising nano metal oxides that are useful for diabetic foot ulcer nanomedical therapy strategies.