Psoralen is an effective active component extracted from Psoraleacorylifolia, which can promote bone formation in osteoporotic animals. However, to the best of our knowledge, its effect on fracture healing has not yet been examined. In the present study, open femur fractures were created in ovariectomy (OVX)-induced osteoporotic mice. OVX mice were treated with psoralen (psoralen+OVX group) or physiological saline (OVX group) by oral gavage. Radiographic and histological results demonstrated progressed callus consolidation in the psoralen+OVX group compared with the OVX group after 10 and 21 days of treatment. Qualitative histological analysis showed that the number of osteoclasts was significantly reduced in the psoralen+OVX group after treatment. Moreover, reverse transcription-quantitative PCR analysis of callus samples showed increased expression of bone morphogenetic protein-2 (BMP-2) and osteoprotegerin (OPG), and decreased expression of receptor activator of nuclear factor-κB ligand (RANKL) at 10 and 21 days post injury in the psoralen+OVX group compared with the OVX group. Furthermore, western blot analysis showed that psoralen significantly increased the expression of estrogen receptor (ER)-α, but had no effect on ER-β expression; these results were further confirmed by immunohistochemistry. To conclude, these results indicated that psoralen may promote callus formation and inhibit osteoclast genesis by increasing BMP-2 and ER-α levels, and OPG/RANKL ratio. Consequently, psoralen could be a possible treatment for osteoporotic fracture-related complications. Copyright: © Huang et al.