Pulmonary arterial hypertension (PAH) is a fatal disease whose molecular mechanism is unknown. The trimethylation of lysine 36 on histone 3 (H3K36me3) catalyzed by SETD2 and the modification of N6-methyladenine (m6A) mRNA mediated by METTL14 play important roles in a variety of normal and pathological biological processes. However, the role of these epigenetic controls in the pathogenesis of PAH remains unclear. In this study, the expression of SETD2 and METTL14 was elevated in pulmonary artery smooth muscle cells (PASMCs) of hypoxia-induced PAH mice. We further constructed a mouse model with SETD2 specific knockout in smooth muscle cells (SETD2SM22α Cre). Our results suggest that the lack of SETD2 in SMCs protected mice from hypoxia-induced PAH and significantly reduced right ventricular systolic pressure (RVSP), right ventricular/left ventricular plus septum [RV/(LV+S)] weight ratio, and pulmonary median width. In addition, the absence of SETD2 in SMCs alleviates the level of METTL14 expression and the m6A RNA methylation level in PAH SMCs. These results obtained from mice suggest that strategies that target the inhibition of SETD2/METTL14 activity may be a viable treatment for PAH in a clinical setting.