Long-term use of glucocorticoids (GCs) is known to be a predominant cause of osteonecrosis of the femoral head (ONFH). Moreover, GCs can mediate apoptosis of various cell types by exaggerating oxidative stress. Previous studies have reported that the AKT pathway might be closely associated with apoptosis and metabolism of osteoblasts in ONFH mediated by GCs. We have previously found that cortistatin (CST) antagonizes oxidative stress and improves cell metabolism as well as apoptosis in several conditions. In this study, we detected that local and systemic CST expression levels were diminished in patients with ONFH compared with femoral neck fracture (FNF). In addition, a GC-induced rat ONFH model was established, which impaired bone quality and angiogenesis and improved osteoblastogenesis in the femoral head. Then, administration of CST attenuated these ONFH phenotypes in this model. Furthermore, osteoblast and endothelial cell lines were cultured and stimulated with dexamethasone (Dex) in the presence or absence of recombinant CST. As a result, Dex induced apoptosis and impaired anabolic metabolism of osteoblasts and suppressed tube formation as well as migration in endothelial cells, while additional treatment with CST reversed this damage to the cells. Moreover, blocking GHSR1a, a well-accepted receptor of CST, or blocking the AKT signaling pathway largely abolished the protective function of CST in Dex-induced disorder of the cells. Taken together, our results indicate that CST has the capability to prevent GC-induced apoptosis and metabolic disorder of osteoblasts in the pathogenesis of ONFH via the GHSR1a/AKT signaling pathway.