Steroid-induced avascular necrosis of the femoral head (SANFH) is a progressive degenerative disease of the hip, primarily due to glucocorticoid (GC)-induced endothelial cell (EC) injury and compromised blood supply. Irisin is an EC-protective mytokine whose receptor is the integrin αVβ5. Caveolin-1 (CAV-1)， a major component of caveolae, causes endothelial dysfunction when phosphorylated. However, the role of irisin and CAV-1 in SANFH remains unclear. In our study, irisin levels decreased but CAV-1 phosphorylation increased in human and mouse SANFH samples. Intraperitoneal irisin injection (250 μg/kg daily) notably reduced GC-induced osteonecrosis, vascular abnormalities, and CAV-1 phosphorylation in SANFH mice. In cultured ECs, GC induced CAV-1 phosphorylation by activating c-Abl via the glucocorticoid receptor, and irisin inhibited GC-induced phosphorylation of c-Abl and CAV-1 via the integrin αVβ5. Inhibition of integrin αVβ5 also abolished the protective effects of irisin on ERK and eNOS signalling, viability, angiogenesis, and migration in ECs. Therefore, our findings indicate that irisin has a protective role against vascular dysfunction in SANFH, possibly mediated by the inhibition of GC-triggered c-Abl-CAV-1 phosphorylation through integrin αVβ5. These findings provide insights into the potential therapeutic applications of irisin in SANFH.