Objective To investigate the protective effect and mechanism of astragaloside Ⅳ (AS-Ⅳ) on the pulmonary arterial hypertension (PAH) model induced by monocrotaline (MCT)/monocrotaline pyrrole (MCTP) in SD rats/human pulmonary artery endothelial cell (HPAEC). Methods In vivo experiment, 60 male SD rats were randomly assigned to control group, PAH model group, AS-Ⅳ low-dose (20 mg/kg) group, AS-Ⅳ medium-dose (40 mg/kg) group, AS-Ⅳ high-dose (80 mg/kg) group, or sildenafil (Sil, 100 mg/kg) group, with 10 rats in each group; except for the control group, PAH rat models were established by single intraperitoneal injection of MCT (60 mg/kg) in other groups. In vitro experiment, HPAECs were randomly assigned to control group, PAH model group, AS-Ⅳ low-dose (10 μmol/L) group, AS-Ⅳ medium-dose (20 μmol/L) group, MCTP＋AS-Ⅳ high-dose (40 μmol/L) group, or p38 mitogen-activated protein kinase (MAPK) signaling pathway inhibitor (SB203580, 5 μmol/L) group; except for the control group, in vitro PAH cell models were established by MCTP (60 μg/mL) induction for 24 h in other groups. In vivo experiments, after 4 weeks of drug intervention, the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) of rats were measured by hemodynamic methods, the right ventricle hypertrophy index was measured by weighing methods, the percentage of pulmonary arteriole wall thickness to outer diameter (WT%) and percentage of the wall area to total vascular area (WA%) were observed by hematoxylin-eosin staining, the expression of cysteine aspartic acid specific protease 3 (caspase 3) protein in lung tissue was observed by immunohistochemistry (IHC), and the apoptosis of lung tissue cells was detected by TUNEL assay. In vitro experiments, JC-1 staining was used to detect the mitochondrial membrane potential in cells, and immunofluorescence was used to detect caspase 3 protein expression. In vitro and in vivo experiments, Western blotting was used to detect the expression of caspase 3, B-cell lymphoma gene 2 (Bcl-2), Bcl-2 associated X protein (Bax), p38 MAPK, and phosphorylated p38 MAPK proteins in lung tissue and HPAECs. Results In vivo experiments, the RVSP, mPAP, and right ventricle hypertrophy index were decreased in the Sil group and each dose group of AS-Ⅳ (all P＜0.01); the WA% and WT% of each dose group of AS-Ⅳ were decreased (all P＜0.01), the expression of caspase 3 protein in lung tissue was decreased (all P＜0.01), and the apoptosis of lung tissue cells was decreased (all P＜0.01). In vitro experiments showed that after intervention with each dose of AS-Ⅳ and SB203580, the mitochondrial membrane potential of HPAEC was increased (all P＜0.01) and the expression of caspase 3 was decreased (all P＜0.01). In vivo and in vitro experiments, each dose of AS-Ⅳ and SB203580 reduced the expression of Bax and phosphorylated p38 MAPK proteins, and increased the expression of Bcl-2 protein (all P＜0.01). Conclusion AS-Ⅳ reduces apoptosis by inhibiting p38 MAPK signaling pathway, improving PAH in SD rats.