Significance This study explores the potential of a phage, PYO ^Sa , for treating Staphylococcus aureus infections in combination with antibiotics. Population dynamic and genomic analysis identified a limitation and potential liability of using PYO ^Sa for therapy. Due to the production of potentially pathogenic atypical small colony variants, PYO ^Sa alone cannot eliminate S. aureus populations. However, we demonstrate that by following the administration of PYO ^Sa with bactericidal antibiotics, this limitation and potential liability can be addressed. The methods used in this investigation to explore the efficacy of combinations of PYO ^Sa and antibiotics for treating S. aureus infections can be employed to evaluate the clinical potential and facilitate the design of treatment protocols for any bacteria and phage that can be cultured in vitro.