Ubiquitin proteasome system (UPS) is the major avenues approach of protein degradation, which is responsible for 80% protein degradation in eukaryotic cells. Recently, UPS is involved in a variety of disease processes and plays a significant role in DNA repair, transcription regulation, autophagy and protein transport. Pulmonary arterial hypertension (PAH) is a disease mainly caused by pulmonary artery endothelial cell (PAEC) dysfunction and pulmonary artery smooth muscle cell (PASMC) excessive proliferation and abnormal apoptosis. These increased pulmonary vascular resistance, vascular remodeling, and finally leading to the failure of right heart. The alteration of pulmonary artery protein ubiquitination occurs at the initial stage of PAH and participates in several cell pathways, such as vasoconstriction, tissue remodeling/angiogenesis, cell migration and calcium signaling. In this review, we mainly introduce the functional changes of UPS in PAH, especially specific E3 ubiquitin ligases with related endoplasmic reticulum stress (ERS), proteolysis-targeting chimeras (PROTACs) and proteasome inhibitors mediated degradation mechanism, providing new ideas for the precise diagnosis and treatment of PAH.