This study aims to investigate the clinical efficacy and underlying mechanism of Huoxue Tongbi Formula in treating patients with steroid-induced osteonecrosis of the femoral head (SONFH) with meridian blockage syndrome. A total of 40 patients with SONFH and meridian blockage syndrome were retrospectively enrolled. Demographic data, clinical efficacy scores (pain and hip joint function), Harris scores, hip joint range of motion, imaging indices (ARCO stage, BUCMXE, bone marrow edema, and joint effusion), symptom/syndrome scores, and coagulation-related physiochemical indices (complete blood count, four coagulation tests, and four thrombosis tests) were collected and compared before treatment and after three months of treatment. Peripheral blood samples from three patients with significant efficacy were subjected to transcriptome sequencing before and after treatment to screen differentially expressed genes (DEGs). GO and KEGG enrichment and PPI network analysis were performed. Genes most relevant to the core phenotype of SONFH with meridian blockage syndrome were identified using Spearman correlation analysis. The results showed that Huoxue Tongbi Formula significantly improved the clinical efficacy scores (including pain and hip joint flexion function), Harris scores, and range of internal and external rotation of the hip (P<0.01). It also maintained stable imaging indices, alleviated various blood stasis-related clinical symptoms (hip pain, fixed pain, lower limb weakness) (P<0.05, P<0.001), and significantly reduced thrombin-antithrombin complex (TAT) levels (P< 0.01). Transcriptome analysis identified 368 DEGs (274 upregulated and 94 downregulated). GO functional enrichment revealed that the biological processes involved by DEGs mainly include positive regulation of tumor necrosis factor production, integrin-mediated signaling pathways, neutrophil chemotaxis, and regulation of tumor necrosis factor production. KEGG enrichment analysis revealed that these DEGs were primarily involved in pathways such as hematopoietic cell lineage, osteoclast differentiation, complement and coagulation cascades, and platelet activation. PPI network analysis combined with correlation analysis identified core genes UBA52 (r=0.83, P<0.05), RACK1 (r=0.88, P<0.05), and RPL19 (r=-0.87, P<0.05) were significantly correlated with blood stasis syndrome scores. CD74 was significantly correlated with osteonecrotic lesions (r=0.95, P<0.05) and TAT (r=0.88, P<0.05). These findings indicate that Huoxue Tongbi Formula ameliorates clinical symptoms and certain imaging indices in SONFH patients with meridian blockage syndrome by regulating hematopoiesis and bone metabolism (inhibiting osteoclast activity) and correcting hypercoagulability (inhibiting coagulation activation). Core genes such as UBA52, RACK1, and RPS3A may be key molecules linking blood stasis syndrome to the regulation of the coagulation-bone metabolism network.