【Abstract】Objective The study aims to investigate the effects of Galectin-3 (Gal3) on the skin abscess development and activation of mast cell (MC) in mice skin infected with methicillin-resistant Staphylococcus aureus (MRSA). Methods Gal3 knockout (Gal3-/-) mice, at 6-8 weeks of age, were subcutaneously injected with MRSA or the same volume of phosphate buffer saline (PBS) PBS, five mice per group. The development and pathological changes of skin abscess were monitored and recorded. The bacterial load in skin tissues with bacterial culturing, the expression of associated cytokines, morphological differences of MC, and the distribution of MC activation marker 5-hydroxytryptamine (5-HT) were detected respectively. Results the inoculation area of the skins in both WT + MRSA and Gal3-/- + MRSA groups showed progressive abscess, accompanied by abscess exudation after subcutaneous infection with MRSA. However, compared to WT + MRSA group, Gal3-/- + MRSA mice got smaller abscess areas (P<0.01) and less infiltrating inflammatory cells in the skin with histopathological observation. The bacterial load in the skin tissues of Gal3-/- + MRSA group was significantly lower than that of WT + MRSA group (P<0.01). Meanwhile, the cytokines including IL-1β, TNF-α, IL-33, TGF-β and IL-10 were significantly less (P<0.05) in Gal3-/- + MRSA mice than that in WT + MRSA mice (P<0.05). MC were active and degranulated in the skin tissue of the WT + MRSA mice, while Gal3-/- + MRSA mice got less degranulated mast cells than WT + MRSA mice (P<0.05). Immunohistochemical staining showed that the expression of 5-HT was significantly increased in the WT + MRSA group, while decreased when Gal3 was deficient in mice. Conclusion Gal3 deficiency can reduce the activation and degranulation of mice skin MC after MRSA infection, which changes inflammatory responses and alleviates the abscess of skin tissue.