Objective: To investigate the preventive mechanism of Buxue Tongluo pill(BTP) against osteonecrosis of femoral head(ONFH) based on network pharmacology and transcriptomics. Methods: We established an ONFH model in SD rats using high dose dexamethasone. Thirty-six rats were randomly divided into six groups, namely normal group, model group, positive group and low-dose group, middle-dose group and high-dose group. Transcriptome sequencing regarding the femoral head was conducted 4 weeks after continuous treatment. Subsequently, mechanism of action of BTP on ONFH determined by integrated network pharmacology. Results: After BTP treatment, 308 genes were significant changed in expression levels, 120 genes being up-regulated and 188 being down-regulated. A total of 108 key targets were targeted for selection. KEGG analysis suggested that various pathways were largely involved in the mechanisms of BTP against ONFH, such as PI3k-Akt signal pathway, cancer, cell cycle and so on. Conclusion: BTP is effective in treating ONFH through multi-components, multi-targets and multi-channels, which may be related to apoptosis mediated by PI3k-Akt signaling pathway.