<p>Multidrug resistant <i>Staphylococcus aureus</i> (MDRSA) is a superbug that shows enormous resistance to many antibiotics. Identified by the World Health Organization as one of the high priority pathogens, there is an urgent need to develop new antibiotic strategies against MDRSA. One such approach is the use of bacteriophages as antimicrobial agents. When bacteriophages are used in combination with antibiotics, phage-antibiotic synergism (PAS) effectively inhibits bacteria. The current study evaluated various phage-antibiotic combinations to determine the optimal PAS activity against 10 clinical isolates of MDRSA, both in vitro and in a burn-induced wound infection mouse model (<i>n</i> = 3/ group). A novel phage, SDAH-01, was isolated locally and characterized. After establishing in vitro antibacterial activity, a burn-induced skin infection mouse model was used to evaluate PAS activity. Wound contraction, bacterial load, and histopathological changes were observed over the duration of treatment. Inflammatory markers (IL-6, TNF-α, VEGF) were evaluated using immunohistochemical methods. Optimal combinations of phages with amoxicillin, azithromycin, and ciprofloxacin significantly inhibited bacterial growth and promoted wound healing as compared to monotherapies. By Day 14, phage-amoxicillin resulted in a 6-log reduction in bacterial load, showing the maximum activity. Similarly, phage-azithromycin and phage-ciprofloxacin combinations showed significant reductions in comparison to monotherapies depicting their improved efficacy. Phage-antibiotic groups also exhibited highest rates of wound contraction, with phage-amoxicillin and phage-azithromycin demonstrating 55% and 50% contraction respectively. Histological analysis indicated improved tissue regeneration and reduced inflammation with combination therapy. This study demonstrates the potential of PAS in effective management of MDRSA infections, suggesting its potential clinical use.</p> Graphical Abstract <p></p>