Staphylococcus aureus is an important pathogen with strong pathogenicity and serious threat to public health. The toxin-antitoxin system is considered to be contributed to the pathogenicity of S. aureus, but the exact pathogenic mechanism remains unknown. Our previous study showed that toxin-antitoxin system SavRS could directly negatively regulate the expression of virulence factors hla and efb, but positively regulate the expression of virulence factors sbi, sak, chp, and scn. Knockout of savRS resulted in a significant increase of virulence in mouse subcutaneous abscess and Galleria mellonella larval infection models. In addition, the disruption of savRS significantly decreased the intracellular survival of S. aureus in macrophages. We also found that the deletion of savRS resulted in increased ability to induce cytokine (TNF-α and IL-6) production.