<p><i>Staphylococcus aureus</i>, particularly methicillin-resistant strains (MRSA), continues to pose a major therapeutic challenge and highlights the need for alternative or supportive treatment strategies. In this study, the recombinant iron-regulated surface determinant E (IsdE) protein was expressed, purified, and used to generate rabbit polyclonal IgG antibodies.</p><p>Antibody specificity was confirmed by ELISA and Western blotting, and functional activity was assessed using an opsonophagocytic assay.</p><p>To evaluate in vivo efficacy, BALB/c mice were challenged with a 5 × 10⁸ CFU dose of MRSA and treated with anti-IsdE IgG. Bacterial burden in internal organs was measured; histopathological changes and survival rates were recorded.</p><p>To investigate the regulation of inflammatory responses by the immune system, levels of inflammatory cytokines (IL-6 and TNF-α) were measured in the serum of the studied mice.</p><p>Treatment with anti-IsdE IgG was associated with reduced bacterial burden in target organs, decreased levels of inflammatory cytokines (IL-6 and TNF-α), improved histopathological findings, and increased survival compared with the control groups. However, vancomycin treatment produced the highest overall protection.</p><p>These findings suggest that antibodies directed against IsdE may contribute to immune-mediated protection under experimental conditions and could be considered as a potential adjunctive strategy alongside antibiotic therapy, pending further validation.</p><p>Further investigations are required to clarify antigen-specific mechanisms and to assess the translational potential of this approach.</p>