Objective This study was conducted to determine the potential of lentinan in protection against methicillin-resistant S. aureus (MRSA) skin infection. Methods Bacterial burden determination and Immunohistochemistry analysis were used to assess the effect of lentinan on antimicrobial infection using a Staphylococcus aureus-infected skin injection model in mice by inoculated with 30μl of 5×10 ⁷ CFU MRSA, and the polymerase chain reaction (RT-PCR) was used to test the effects of lentinan on mRNA expression of IL-33 and chemokine KC at skin abscess in mice. Results Skin wound sections from lentinan -treated in mice was significantly milder than that in control group. Bacterial burden determination and immunohistochemistry analysis showed that significantly decrease bacterial burden and significant increase in CD11b+Gr1+ neutrophils recruitment infiltration, was noted in infectious wounds from lentinan -treated mice. At the same time, mRNA expression of IL-33 and chemokine KC was promptly increased in cutaneous wound tissues when challenged by lentinan. Conclusion Lentinan plays an essential effect of anti-MRSA skin infection in mice.