Empagliflozin (Empa), an inhibitor of the sodium-glucose cotransporter 2 (SGLT2), has been shown to have cardiovascular benefits in patients with type 2 diabetes. Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary artery remodeling that leads to right ventricular (RV) failure. The NOTCH3 signaling pathway has been implicated in regulating pulmonary arterial smooth muscle cell (PASMC) proliferation in PAH. We aim to evaluate the underlying mechanism of Empa, hypothesizing that Empa reverse pulmonary artery remodeling by suppressing NOTCH3 signaling. In this study, the model of hypoxic-PAH mice was treated with or without the administration of Empa. The expression of proteins was analyzed by western blot and immunohistochemistry. The results showed that hypoxic-PAH mice displayed characteristics of PAH and an enlarged RV, whereas Hypoxic-PAH mice treated with Empa alleviated RV hypertrophy and reduced vascular wall thickness. In addition, pulmonary arterial cells were isolated from IPAH patients and treated with Empa. Overexpression of NOTCH3 and Hes Family BHLH Transcription Factor 5 (Hes5), the downstream genes of NOTCH3 signaling, were observed in isolated PASMCs of IPAH patients, and Empa significantly inhibited the proliferation and migration of IPAH-PASMCs by suppressing NOTCH3 and Hes5 expressions. In summary, the results indicated that Empa could reverse vascular remodeling via the inhibition of NOTCH3 signaling pathway. Therefore, the present study provided new insight into the potential of Empa as a therapeutic target for PAH.