This study systematically elucidated the scientific connotation of Jianpi Huogu Formula in treating phlegm-stasis blocking collaterals syndrome in steroid-induced osteonecrosis of the femoral head (SONFH) by integrating clinical transcriptomics, lipid metabolomics, and biomolecular network mining techniques. The invigorating the spleen and resolving phlegm group (Codonopsis Radix, Atractylodis Macrocephalae Rhizoma, Poria, and Citri Reticulatae Pericarpium) targeted effective target genes such as ALDH7A1 and ACOX1 through 115 chemical components, regulated the AMPK and sphingolipid signaling pathways, significantly reduced the levels of diacylglycerol (DAG) and cholesterol esters, and effectively corrected lipid metabolism disorders. The activating blood circulation and dredging collaterals group (Angelicae Sinensis Radix, Chuanxiong Rhizoma, Paeoniae Radix Rubra, Achyranthis Bidentatae Radix, and Cinnamomi Ramulus) exerts effects through 197 chemical components by intervening in the chemokine and NOD-like receptor pathways, inhibiting the formation of neutrophil extracellular traps (NETs), downregulating inflammatory factor expression, and promoting vascular function repair. The tonifying the kidney and strengthening bones group (Rehmanniae Radix Praeparata and Cervi Cornu) regulated the PI3K/Akt and Ras/MAPK signaling pathways, inhibited osteoclast differentiation genes CTSK and MMP9, and facilitated the reconstruction of bone homeostasis. Transcriptomic and lipid metabolomic analyses were performed on clinical blood samples collected before and after treatment with Jianpi Huogu Formula. Multi-omics integration revealed that the three efficacy groups synergistically constructed a multidimensional network involving "lipid metabolism-immunity-bone homeostasis". A total of 594 differentially expressed effector genes (367 downregulated and 227 upregulated) were identified via clinical transcriptomics, and 179 differential lipid metabolites (mainly triglycerides and DAG) associated with the formula's efficacy were identified via lipid metabolomics. Together with 2 657 disease/syndrome-related genes, a "disease-syndrome-symptom-formula" association network was constructed. Topological eigenvalue analysis and functional mining indicated that the core network targets of Jianpi Huogu Formula in intervening SONFH mainly regulated signaling pathways such as osteoclast differentiation, apoptosis, Ras, MAPK, PI3K/Akt, and p53, thereby inhibiting osteoclast activity, promoting osteoblast proliferation, balancing bone resorption and formation, and improving the bone marrow microenvironment. This study systematically reveals the scientific basis of Jianpi Huogu Formula in intervening in the pathological process of SONFH through the synergistic action of "lipid metabolism reprogramming-transcriptional regulatory network" from three key dimensions, i. e., lipid metabolism, inflammation, and bone remodeling. It fully demonstrates the holistic advantages of traditional Chinese medicine (TCM) formulas in multi-component, multi-target, and multi-pathway coordinated regulation, and provides an innovative perspective and data support for elucidating the mechanism of TCM in the prevention and treatment of SONFH.