Objective To investigate the regulation of S100A11-RAGE on the hypertrophy and extracellular matrix metabolism of chondrocytes by P38MAPK signal pathway in mice. Methods Different concentrations of exogenous S100A11 and cartilage cells were incubated for 48 h. Expressions of MMP-13, ADAMTS-5, type II and type X collagen were detected by PCR, Western Blot and immunohistochemistry, respectively. Anti-P38 and cartilage cells were incubated for 12 h, and then incubated 48 h after exogenous S100A11 was added. Expressions of MMP-13, ADAMTS-5, type II and type X collagen were detected. Results The expression of MMP-13, ADAMTS-5 and type X collagen of cartilage cells increased with the increase of the concentration of exogenous S100A11, and was significantly higher than that of the control group. The expression of type Ⅱ collagen decreased with the increase of the concentration of exogenous S100A11, and was significantly lower than that of the control group. After the addition of Anti-P38, the expressions of MMP-13, ADAMTS-5 and type X collagen were significantly lower than that of S100A11 alone treatment group, and the expression of type Ⅱ collagen was significantly higher than that of S100A11 alone treatment group. Conclusions S100A11-RAGE can regulate the hypertrophy and extracellular matrix degradation of chondrocytes in mice, and the mechanism may be related to the induced MMP-13, ADAMTS-5 and type X collagen expression and reduce type Ⅱ collagen expression through the P38 MAPK signal pathway.