Celastrol has recently been identified as a prospective new treatment for obesity and several metabolic complications. However, the effect of Celastrol in osteoporosis (OP) remains unknown. In this study, we demonstrated that Celastrol promotes osteoblast differentiation and prevents adipocyte differentiation in bone marrow mesenchymal stem cells (BM-MSCs) in vitro. Mechanistically, Celastrol was able to control the differentiation of BM-MSCs by stimulating PGC-1α signaling. Moreover, administration of Celastrol could alleviate bone loss and bone marrow adipose tissue (MAT) accumulation in ovariectomized (OVX) mice and aged mice. Together, these results recommended that Celastrol could regulate BM-MSCs fate and bone-fat balance in OP and skeletal aging by stimulating PGC-1α, which might act as a possible therapeutic target for OP and for the prevention of skeletal aging.