PURPOSE: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease characterized by elevated pulmonary arterial pressure and resistance. 18β-Glycyrrhetinic acid (18β-GA), a major bioactive component in Glycyrrhiza glabra L., exhibits various pharmacological activities. Although 18β-GA has been found to alleviate PH, the underlying mechanisms are still unclear. This study was aimed to elucidate the molecular processes by which 18β-GA attenuates PH. PATIENTS AND METHODS: A monocrotaline-induced PH rat model was created, and cardiac function and pulmonary arterial pressure were assessed. Rat blood markers were analyzed via enzyme-linked immunosorbent assay, and protein levels of Vanin-1, NF-κB, IL-6, TNF-α, PPAR-γ, and iNOS in lung tissue were determined by western blotting. A hypoxia-induced pulmonary artery smooth muscle cell (PASMCs) proliferation model was created, and cell proliferation and migration were evaluated using CCK-8 and scratch wound assays. Cell cycle, apoptosis, and mitochondrial membrane potential were assessed via flow cytometry, and protein levels were measured using western blotting. RESULTS: PH rats treated with, 18β-GA exhibited reduced mean pulmonary arterial pressure (mPAP) and delayed pulmonary vascular remodeling. In lung tissue, Vanin-1, NF-κB, IL-6, and TNF-α were downregulated, while PPAR-γ and iNOS were upregulated. PASMCs treated with 18β-GA exhibited reduced hypoxia-induced proliferation and increased apoptosis. In addition, NO levels in the supernatant of PASMCs were elevated, and Vanin-1 and NF-κB were downregulated, whereas PPAR-γ and iNOS were upregulated. CONCLUSION: Our findings reveal a novel mechanism by which 18β-GA attenuates PH by improving pulmonary vascular remodeling and inhibiting PASMCs proliferation via the Vanin-1/L-Arg/NO pathway.