ABSTRACT Background Osteoporosis is a condition in where bones gradually become thin and weak, making them more susceptible to fractures. Columbianadin has showed potential anti‐inflammatory and antioxidant effect. In this experimental study, anti‐osteoporosis effect of Columbianadin against glucocorticoid induced osteoporosis in rats. Methods In this study, Sprague Dawley (SD) rats were used and osteoporosis was induced by administering dexamethasone (DEX) at a dosage of 2.5 mg/kg/day. Following induction, the rats were treated orally with different doses of columbianadin. The body weight, organ (femoral, vagina and uterus) weights were measured. The bone parameters, antioxidant, cytokines, hormones were evaluated. Results Columbianadin improved body weight and altered the organ weight such as femoral, vagina and uterus. It also modulated the various bone related parameters including bone mineral density (BMD), tissue mineral density (TMD), bone mineral content (BMC), tissue mineral content (TMC); bone parameters like tartrate‐resistant acid phosphatase (TRAP), β ‐C‐terminal telopeptide of type I collagen (β‐CTX), osteocalcin (OC), bone gla protein (BGP), acid phosphatase (ACP), alkaline phosphatase (ALP). Additionally, Columbianadin influence hormone level such as estradiol (E 2 ) and parathyroid hormone (PTH) and enhanced antioxidant defense via modulating glutathione peroxidase (GPx), thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH). It also regulated the cytokines parameters like tumor necrosis factor‐ α (TNF‐α), interleukin‐1β (IL‐1β), interleukin‐6 (IL‐6), insulin‐like growth factor (IGF), transforming growth factor‐β (TGF‐β). Furthermore, columbianadin modulated the levels of receptor activator of nuclear factor‐κB ligand (RANKL), osteoprotegerin (OPG) and OPG/RANKL ratio. Columbianadin also altered mRNA expression of ALP, OPN, runt‐related transcription factor 2 (RunX2), OCN, bone morphogenetic proteins (BMP)‐2, 4, 6, 7, 9, B‐cell lymphoma 2 (BcL‐2), B‐cell lymphoma‐extra‐large (BcLxL), Inhibitor of Apoptosis Protein (IAP) 1, 2, X‐linked Inhibitor of apoptosis Protein (XIAP), caspase‐3,6,7,9, respectively. Conclusion The finding of the study clearly demonstrates that columbianadin exerts a significant antiosteoporosis effect against glucocorticoid‐induced osteoporosis in rats.