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Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized primarily by sustained pulmonary vasoconstriction, pulmonary vascular remodeling, and elevated pulmonary artery pressure. Recent emerging studies have indicated that mitochondria-endoplasmic reticulum (ER) membrane (MAM) is increasingly implicated in pathogenesis of pulmonary hypertension (PH). Dysfunction of mitochondria or ER can trigger a series of pathological processes, including disrupted intracellular Ca2+ homeostasis, oxidative stress, ER stress, and inflammation, which in turn drive dysfunction of pulmonary artery smooth muscle (PASMCs) and endothelial cells (PAECs). This review article aims to systematically evaluates the pathogenic mechanisms of the MAM in PH, covering the latest research advances in mitochondrial dynamic disorders, Ca2+ homeostasis, ER stress, oxidative stress, cellular metabolic reprogramming, and inflammatory responses. Special focus is placed on the structural and functional regulatory mechanisms of MAMs and their roles in pulmonary vascular functional and structural dysfunction. Furthermore, the current review also discusses the potential of new and efficacious therapeutic strategies targeting mitochondrial dysfunctions and ER stress for treatments of PH.