The Na⁺/Ca²⁺ exchanger type-1 (NCX1) is a bidirectional transporter controlled by membrane potential and transmembrane gradients of Na⁺ and Ca²⁺, which plays an important role in intracellular Ca²⁺ homeostasis and Ca²⁺ signaling. We found that NCX1 was upregulated in the pulmonary arteries of mice exposed to chronic hypoxia (10% O₂ for 4 weeks). In this study, we investigated the pathophysiological role of NCX1 in hypoxia-induced pulmonary arterial hypertension (PAH), using NCX1-heterozygous (NCX1^+/−) mice, in which NCX1 expression is reduced by half, and specific NCX1 inhibitors (SEA0400, KB-R7943). After exposure to 10% O2 for 4 weeks, right ventricular systolic pressure (RVSP) and right ventricular (RV) hypertrophy were attenuated in NCX1^+/− mice compared with wild-type mice. Furthermore, continuous administration of NCX inhibitors to wild-type mice by osmotic pumps significantly suppressed hypoxia-induced increase in RVSP. SEA0400 also attenuated pulmonary vessel muscularization, with a slight reduction in RV hypertrophy. These findings indicate that the upregulation of NCX1 contributes to the development of hypoxia-induced PAH, suggesting that NCX1 inhibition might be a novel approach for the treatment of PAH.