Background Pulmonary arterial hypertension (PAH) is characterized by suppressing apoptosis and enhancing cell proliferation in the vascular wall. Inducing pulmonary artery smooth muscle cells (PASMC) apoptosis had been regarded as a therapeutic approach for PAH. Oridonin can cause apoptosis in many cell lines, while little has been done to evaluate its effect on PASMC.Methods Thirty male Sprague-Dawley rats were randomly assigned to three groups: normal control (NC); hypoxia-hypercapnia (HH); Hypoxia-hypercapnia + oridonin (HHO). Flats were exposed to hypoxia-hypercapnia for four weeks. Cultured human PASMC (HPASMC) were assigned to three groups: normoxia (NO); hypoxia (HY); hypoxia+ oridonin (HO). The mean pulmonary artery pressure, mass ratio of right ventricle over left ventricle plus septum (RV/(LV+S)), the ratio of thickness of the pulmonary arteriole wall to vascular extal diameter (WT%) and the ratio of the vessel wall area to the total area (WA%) were measured. Morphologic changes of pulmonary arteries were observed under light and electron microscopes. The apoptotic characteristics in vitro and in vivo were detected. Results The mPAP, RV/(LV+S), WT%, and WA% in the HH group were significantly greater than those in the NC (P <0.01) and HHO groups (P <0.01); the activities of caspase-3 and caspase-9, and the expressions of Bex, cyt-C and apoptotic index (AI) in the group HH were less than those in the NC and HHO groups; and the expression of Bcl-2 in group HH was greater than that in the NC and HHO groups. HPASMC mitochondrial membrane potentials in group HO was lower than in group HY (P <0.01), and cyt-C in the cytoplasm, AI, and caspase-9 in the HO group were greater than that in the HY group (P <0.01), but the expression of Bcl-2 in the HO group was less than that in the HY group (P <0.05). Conclusions The results suggest that oridonin can lower pulmonary artery pressure effectively, and inhibit pulmonary artery structural remodeling by inducing smooth cell apoptosis via a mitochondria-dependent pathway.