Background: Osteonecrosis of the femoral head (ONFH) is a challenging global health issue with an unclear pathogenesis, complicating the development of effective treatment strategies. Bone marrow edema (BME) is a critical imaging indicator of ONFH progression, yet its underlying mechanisms remain poorly understood. Methods: Bioinformatics was employed to identify gene characteristic of BME in ONFH patients. Expression of PTGS2 was validated in these patients through Western blot and ELISA assays. Clinical relevance was assessed by analyzing the correlation between PTGS2 expression levels and pain severity as well as the timing of total hip replacement surgery. In addition to GSE74089, we externally validated PTGS2 in an independent GEO cohort (GSE123568, human serum; GPL15207) using single‐gene receiver operating characteristic (ROC) analysis. Results: Six hundred and eighty‐eight overlapping targets were identified for ONFH and BME, with 15 key targets shared with XLGBC, including PTGS2, IGFBP3, MCL1, TNF, F7, PLA2G4A, PRKCA, MMP1, and PTGER3. GO and KEGG enrichment analyses indicated that XLGBC exerts its effects mainly through pathways related to inflammation, pain, angiogenesis, and bone metabolism, notably involving VEGF signaling, arachidonic acid metabolism, and MAPK pathways. Molecular docking revealed strong binding between XLGBC compounds and the target genes. ELISA results indicated that higher PTGS2 levels correlated with increased pain severity in ONFH patients, and Western blot analysis showed significantly elevated PTGS2 in ONFH patients compared to controls, with levels decreasing after XLGBC treatment. Patients with higher PTGS2 expression showed shorter times to hip replacement surgery, suggesting faster disease progression. In the external cohort (GSE123568), PTGS2 showed good diagnostic discrimination for ONFH versus controls (AUC = 0.86), supporting the robustness of our bioinformatics findings. Conclusions: PTGS2 is an important gene in ONFH with BME, influencing pain and disease progression. Monitoring PTGS2 expression may help to assess symptom severity and inform surgical timing in ONFH patients.