While previous studies have demonstrated the role of ubiquitin-conjugating enzyme 2C (UBE2C) in promoting β-cell proliferation and cancer cell lineage expansion, its specific function and mechanism in bone marrow mesenchymal stem/stromal cells (BMSCs) growth and differentiation remain poorly understood. Our findings indicate that mice with conditional Ube2c deletions in BMSCs and osteoblasts exhibit reduced skeletal bone mass and impaired bone repair. A significant reduction in the proliferative capacity of BMSCs was observed in conditional Ube2c knockout mice, with no effect on apoptosis. Additionally, conditional Ube2c knockout mice exhibited enhanced osteoclastic activity and reduced osteogenic differentiation. Furthermore, human BMSCs with stable UBE2C knockdown exhibited diminished capacity for osteogenic differentiation. Mechanistically, we discovered that UBE2C binds to and stabilizes SMAD1/5 protein expression levels. Interestingly, UBE2C's role in regulating osteogenic differentiation and SMAD1/5 expression levels appears to be independent of its enzymatic activity. Notably, UBE2C regulates osteogenic differentiation through SMAD1/5 signaling. In conclusion, our findings underscore the pivotal role of UBE2C in bone formation, emphasizing its contribution to enhanced osteogenic differentiation through the stabilization of SMAD1/5. These results propose UBE2C as a promising target for BMSC-based bone regeneration.