OBJECTIVE: Steroid-induced osteonecrosis of the femoral head (SONFH) is a debilitating bone condition associated with femoral head collapse and hip joint dysfunction. The pathogenesis of SONFH is still not fully elucidated. This study aims to explore the role of mitochondrial cardiolipin metabolism disruption in SONFH and the potential protective effects of simvastatin (SIM). METHODS: Osteoblasts were cultured in vitro under high concentrations of dexamethasone (DEX) to mimic the effects of glucocorticoid exposure seen in SONFH. Mitochondrial structural changes and cardiolipin distribution were examined using transmission electron microscopy and confocal microscopy. Osteoblast proliferation and apoptosis were assessed using CCK-8 assays and flow cytometry. Mitochondrial cardiolipin content was quantified by ELISA, while cytochrome c (Cyt-c) expression was measured through Western blotting. Mitochondrial staining with NAO was analyzed using confocal microscopy and flow cytometry. RESULTS: DEX exposure led to mitochondrial cardiolipin metabolism disorder and redistribution, resulting in significant mitochondrial structural damage. This disruption was associated with increased release of Cyt-c into the cytoplasm, which correlated with heightened osteoblast apoptosis. SIM treatment mitigated these effects, reducing osteoblast apoptosis by preserving mitochondrial function and modulating cardiolipin content and distribution. CONCLUSION: This study demonstrates, for the first time, that glucocorticoid-induced disruptions in mitochondrial cardiolipin metabolism contribute to the pathogenesis of SONFH by inducing Cyt-c release and subsequent osteoblast apoptosis. SIM exerts a protective effect by preserving mitochondrial integrity and function, offering a potential therapeutic avenue for treating hormone-induced osteoblast damage in SONFH.