Osteonecrosis of the femoral head (ONFH) is a disease that is commonly seen in the clinic, but its detection rate remains limited, especially at the early stage. We developed an ultrasound molecular imaging (UMI) approach for early diagnosis of ONFH by detecting the expression of integrin α_vβ₃ during the pathological changes in steroid-induced osteonecrosis of the femoral head (SIONFH) in rat models. The integrin α_vβ₃-targeted PLGA or lipid microbubbles modified with iRGD peptides were fabricated and characterized. Their adhesion efficiency to mouse brain microvascular endothelial cells in vitro was examined, and the better LIPO_iRGD was used for further in vivo molecular imaging of SIONFH rats at 1, 3 and 5 weeks; revealing significantly higher UMI signals could be observed in the 3-week and 5-week SIONFH rats but not in the 1-week SIONFH rats in comparison with the non-targeted microbubbles (32.75 ± 0.95 vs. 0.17 ± 0.09 for 5 weeks, p < 0.05; 5.60 ± 1.31 dB vs. 0.94 ± 0.81 dB for 3 weeks, p < 0.01; 1.13 ± 0.13 dB vs. 0.73 ± 0.31 dB for 1 week, p > 0.05). These results were consistent with magnetic resonance imaging data and confirmed by immunofluorescence staining experiments. In conclusion, our study provides an alternative UMI approach to the early evaluation of ONFH.