Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious complication caused by the application of bisphosphonates (BPs) which are widely used in bone metastasis, osteoporosis and other metabolic bone diseases. Since bone marrow-derived mesenchymal stem cells (BMSCs) dysfunction potentially plays a critical role in the development of BRONJ, purposefully improving the function of BMSCs may help reduce the symptoms of BRONJ. Apoptosis repressor with caspase recruitment domain (ARC) can inhibit cell apoptosis and cell death, and was confirmed to possess an obvious reparative function in damaged tissues recently. Therefore, we aimed to investigate whether transplantation of ARC-overexpressing BMSCs had a therapeutic effect on BRONJ and explored possible mechanisms. First, we successfully established the BRONJ rat model and confirmed that BRONJ-derived BMSCs showed decreased proliferation and osteogenic differentiation ability. However, ARC-overexpressing BMSCs showed a significant therapeutic effect on BRONJ by promoting osteogenesis and inhibiting osteoclasts. The BRONJ tissue treated with ARC-overexpressing BMSCs also showed a decreased level of cell apoptosis. Further the RNA sequencing and bioinformatics results suggested that ARC can regulate BMSCs by inhibiting the TNF-α (tumor necrosis factor-α) pathway increased in the BRONJ samples and may alleviate the disease by reducing pro-inflammatory potential of BRONJ-derived BMSCs. In summary, ARC-overexpressing BMSCs can effectively repair BRONJ necrotic bone tissue which provides new ideas for the clinical treatment of BRONJ.