Mesenchymal stem cells (MSCs) are a promising cell resource for tissue engineering. Sry‐related high‐mobility group box 11 (Sox11) plays critical roles in neural development and organogenesis. In the present study, we investigated the role of Sox11 in regulating trilineage differentiation (osteogenesis, adipogenesis, and chondrogenesis) and migration of MSCs, and explored the effect of systemically administrated Sox11‐modified MSCs on bone fracture healing using the rat model of open femur fracture. Our results demonstrated that Sox11 overexpression increased the trilineage differentiation and migration of MSCs, as well as cell viability under oxidative stress. The effect of Sox11 on osteogenesis was confirmed by ectopic bone formation assay conducted in nude mice. In addition, we found that Sox11 could activate the bone morphogenetic protein (BMP)/Smad signaling pathway in MSCs. By dual‐luciferase reporter assay, we also demonstrated that Sox11 could transcriptionally activate runt‐related transcription factor 2 (Runx2) and CXC chemokine receptor‐4 (CXCR4) expression. The activation of the BMP/Smad signaling pathway and Runx2, CXCR4 expression may have a synergic effect, which largely contributed to the effect of Sox11 on MSC fate determination and migration. Finally, using an open femur fracture model in rats, we found that a larger number of MSCs stably expressing Sox11 migrated to the fracture site and improved bone fracture healing. Taken together, our study shows that Sox11 is an important regulator of MSC differentiation and migration, and Sox11‐modified MSCs may have clinical implication for accelerating bone fracture healing, which can reduce the delayed unions or nonunions.—Xu, L., Huang, S., Hou, Y., Liu, Y., Ni, M., Meng, F., Wang, K., Rui, Y., Jiang, X., Li, G. Sox11‐modified mesenchymal stem cells (MSCs) accelerate bone fracture healing: Sox11 regulates differentiation and migration of MSCs. FASEB J. 29, 1143‐1152 (2015). www.fasebj.org