Mesenchymal stem cells (MSCs) with multipotential differentiation capacity can differentiate into bone cells under specific conditions and can be used to treat osteonecrosis (ON) of the femoral head (ONFH) through cell transplantation. The current study aims to explore the role of bone marrow (BM) MSCs (BMSCs)-derived exosomes carrying microRNA-122-5p (miR-122-5p) in ONFH rabbit models. First, rabbit models with ONFH were established. ONFH-related miRNAs were screened using the Gene Expression Omnibus (GEO) database. A gain-of-function study was performed to investigate the effect of miR-122-5p on osteoblasts and BMSCs and effects of exosomes carrying miR-122-5p on ONFH. Co-culture experiments for osteoblasts and BMSCs were performed to examine the role of exosomal miR-122-5p in osteoblast proliferation and osteogenesis. The target relationship between miR-122-5p and Sprouty2 (SPRY2) was tested. MiR-122, significantly decreased in ONFH in the GSE89587 expression profile, was screened. MiR-122-5p negatively regulated SPRY2 and elevated the activity of receptor tyrosine kinase (RTK), thereby promoting the proliferation and differentiation of osteoblasts. In vivo experiments indicated that bone mineral density (BMD), trabecular bone volume (TBV), and mean trabecular plate thickness (MTPT) of femoral head were increased after over-expressing miR-122-5p in exosomes. Significant healing of necrotic femoral head was also observed. Exosomes carrying over-expressed miR-122-5p attenuated ONFH development by down-regulating SPRY2 via the RTK/Ras/mitogen-activated protein kinase (MAPK) signaling pathway. Findings in the present study may provide miR-122-5p as a novel biomarker for ONFH treatment.