Glucocorticoids induced osteoporosis (GIOP) is a global concern without effective therapies. The present study investigated the potential of the umbilical cord-derived mesenchymal stem cells (UCMSCs) and traditional medicine Piper longum L. in the reversal of GIOP. Twelve-week-old female Swiss Albino mice were subjected to the dexamethasone treatment for 4 weeks to induce GIOP. Further, the mice were randomized into four different groups for treatment, viz., phosphate buffered saline (PBS), UCMSCs, P. longum L. aqueous extract through feed, and a combination of UCMSCs and P. longum L. extract. Post therapy, GIOP mice regained the weight and hair loss in the UCMSCs and P. longum L. extract group. ALP activity and mRNA expression of RunX2, ALP, and OPN were significantly increased. Micro-CT analysis revealed remarkable improvement in key parameters such as bone volume, bone surface density, tissue surface, trabecular thickness, and number. Our results unequivocally demonstrate that a combination of the UCMSCs and P. longum L. is highly effective in the reversal of GIOP as compared to P. longum L. or UCMSCs alone. The therapeutic effect can be attributed to the osteogenic and paracrine potential of UCMSCs and the anti-inflammatory effect of P. longum L.