The emergence of antibiotic resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) reminds us an urgent need to develop a new immune-modulating agent for preventing S. aureus infection. In this study, we found that herbal medicines, honokiol and magnolol, caused a significant cellular immune modulatory effect during S. aureus infection. In mouse macrophages, these compounds drove upregulation of an antioxidant effect in response to S. aureus, resulting in a dampened total cellular reactive oxygen species (ROS) production and decreased production of inflammatory cytokines/chemokines, whereas honokiol induced increased types I and III interferon messenger RNA (mRNA) expression levels in response to MSSA infection. Moreover, the internalization of S. aureus by human alveolar epithelial cells was inhibited by these compounds. Furthermore, honokiol and magnolol treatment promoted a delay in killing during MSSA infection in Caenorhabditis elegans, suggesting antimicrobial function in vivo. In conclusion, honokiol and magnolol may be considered as attractive immune-modulating treatment for S. aureus infection.