This work was to investigate potential roles of HMGB1‐mediated ERK pathway in the healing process of bone fracture. Rat tibial fracture models were established and divided into control (rats with normal saline), HMGB1 (rats with HMGB1), and HMGB1+ PD98059 groups (rats with HMGB1 and 1 mg/kg of ERK1/2 inhibitor PD98059) with 30 rats per each. The healing of rats' fracture was observed by X‐ray films, the morphological changes of bone fractures by HE staining, the callus formation by micro‐CT and biomechanical test, and the expression of osteogenesis‐related genes, HMGB1 and ERK‐related proteins by qRT‐PCR and Western blot. Rats in the HMGB1 group was increased in X‐ray scores, peak torque, torsional stiffness, and the bone volume fraction (bone volume/total volume, BV/TV); meanwhile, those rats presented elevations in osteogenesis‐related genes and HMGB1 expressions, as well as p‐ERK/ERK ratio. However, rats in the HMGB1+ PD98059 group was significantly reduced in X‐ray score, peak torque, torsional stiffness, and BV/TV, as well as the expression of osteogenesis‐related genes and the ratio of p‐ERK/ERK, as compared to those from HMGB1 group. HMGB1 could promote the expressions of osteogenesis‐related genes and accelerate the healing process of fracture via activation of the ERK signaling pathway.