To explore the role and mechanism of signal molecule high mobility group box protein 1 (HMGB1) mediated by Toll-like receptor 2 (TLR2) in a murine asthma model. Fourteen specific pathogen free (SPF) female C57 and TLR2(-/-) mice each were randomly divided into 4 groups of C57 control, C57 asthma, TLR2(-/-) control and TLR2(-/-) asthma (n = 7 each). The animals were sensitized and challenged with ovalbumin (OVA) for asthmatic modeling. The same amount of normal saline was used in the control group. The supernatant of bronchoalveolar lavage fluid (BALF) was collected for detecting the level of HMGB1 by enzyme-linked immunosorbent assay (ELISA). And the expression of HMGB1 in lung tissue was detected by Western blot and immunohistochemistry. Asthmatic murine model was successfully established. The level of HMGB1 in the BALF of C57 asthma group was significantly higher than that in C57 control, TLR2(-/-) asthma and TLR2(-/-) control groups ((59.0 ± 13.9) vs (42.3 ± 1.6), (47.5 ± 2.3), (42.4 ± 1.4) ng/L; P = 0.001, 0.001, 0.037) . The results of immunohistochemistry showed that the marker of HMGB1 in lung tissue was less than those in the C57 control and TLR2(-/-) control groups. However, the C57 asthma and TLR2(-/-) asthma groups were obviously more and they were located in airway epithelium. Western blot showed that the expression of HMGB1 was significantly higher in C57 asthma group than that in the C57 control, TLR2(-/-) asthma and TLR2(-/-) control groups (0.92 ± 0.29 vs 0.18 ± 0.09, 0.31 ± 0.16, 0.21 ± 0.14; P = 0.007, 0.022, 0.009). HMGB1 promotes the airway inflammation mediated by TLR2. And it may participate in the pathogenesis of asthma.