Icariin is the major active ingredient in Herba epimedii which is a commonly used Chinese herbal medicine for the treatment of osteoporosis. The present study aims to evaluate the osteoprotective effect of Icariin in glucocorticoid-induced osteoporosis in vivo and investigate the effect of Icariin on glucocorticoid-induced osteocyte apoptosis in vitro. A total of 48 female Sprague-Dawley rats were used. Glucocorticoid-induced osteoporosis was induced by daily injections of dexamethasone (0.1 mg/kg, daily, s.c.) for 60 days, whereas sham animals were injected daily with vehicle. At the end of the osteoporosis development period, osteoporotic rats were randomized to receive: vehicle (n = 8), Icariin (5,125 mg/kg, i.g.; n = 8), or alendronate (0.03 mg/kg, s.c.; n = 8) for 12 weeks. Sham animals were treated with vehicle for 12 weeks. At the beginning and at the end of treatments, animals were examined for bone mineral density. Serum bone-alkaline phosphatase and carboxy-terminal collagen cross links were measured. Primary osteocytes were isolated, and apoptosis was determined by trypan-blue assay. Interaction between Icariin and estrogen receptor and prosurvival signaling pathways activated by Icariin were also investigated. Icariin showed a comparable efficacy with alendronate in increasing bone mass. Icariin significantly increased bone-alkaline phosphatase (bone formation marker) and reduced carboxy-terminal collagen cross links (bone resorption marker). In vitro studies demonstrated that Icariin significantly prevented GC-induced apoptosis in osteocytes by activating ERK signaling via estrogen receptor. Our results suggest that Icariin might exert osteoprotective effect by maintaining osteocyte viability, thereby, regulating bone remodeling. Furthermore, our study provides preclinical evidence for the efficacy of Icariin for management of Glucocorticoid-induced osteoporosis.