BACKGROUND: Hypoxic Pulmonary Hypertension (HPH), a prevalent disease in highland areas, is a crucial factor in various complex highland diseases with high mortality rates. Zhishi-Xiebai-Guizhi decoction (ZXGD), traditional Chinese medicine with a long history of use in treating heart and lung diseases, lacks a clear understanding of its pharmacological mechanism. OBJECTIVE: This study aimed to investigate the pharmacological effects and mechanisms of ZXGD on HPH. METHODS: We conducted a network pharmacological prediction analysis and molecular docking to predict the effects, which were verified through experiments. RESULTS: Network pharmacological analysis revealed 51 active compounds of ZXGD and 701 corresponding target genes. Additionally, there are 2,116 targets for HPH, 311 drug-disease co-targets, and 17 core-targets. GO functional annotation analysis revealed that the core targets primarily participate in biological processes such as apoptosis and cellular response to hypoxia. Furthermore, KEGG pathway enrichment analysis demonstrated that the core targets are involved in several pathways, including the phosphatidylinositol-3 kinase/protein kinase B (PI3K/Akt) signaling pathway and Hypoxia Inducible Factor 1 (HIF1) signaling pathway. In vivo experiments, the continuous administration of ZXGD demonstrated a significant improvement in pulmonary artery pressure, right heart function, pulmonary vascular remodeling, and pulmonary vascular fibrosis in HPH rats. Furthermore, ZXGD was found to inhibit the expression of PI3K, Akt, and HIF1α proteins in rat lung tissue. CONCLUSION: In summary, this study confirmed the beneficial effects and mechanism of ZXGD on HPH through a combination of network pharmacology and in vivo experiments. These findings provided a new insight for further research on HPH in the field of traditional Chinese medicine.