INTRODUCTION: Sildenafil, a selective phosphodiesterase 5 inhibitor, modulates vascular dysfunction, with hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) proliferation, migration, and invasion closely implicated in vascular remodeling in persistent pulmonary hypertension of the newborn (PPHN). This study aimed to assess sildenafil's protective effects against PPHN and elucidate underlying molecular pathways. METHODS: Cell Counting Kit-8, wound healing, and Transwell assays evaluated rat PASMC proliferation, migration, and invasion under hypoxia. A rat PPHN model assessed sildenafil's impact on right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), and vascular remodeling. JAK2/STAT3 signaling was analyzed via Western blotting. RESULTS: Sildenafil significantly inhibited hypoxia-induced PASMC proliferation, migration, and invasion. In addition, sildenafil reduced RVSP, RVH, and vascular remodeling in PPHN. Further, sildenafil decreased JAK2 and STAT3 phosphorylation in hypoxia-exposed PASMCs and the PPHN rat model. The JAK2/STAT3 pathway agonist colivelin reversed sildenafil's suppressive effects on PASMC proliferation, migration, invasion, as well as RVSP, RVH, and vascular remodeling in PPHN. CONCLUSIONS: Sildenafil protects against PPHN by inhibiting PASMC proliferation, migration, and invasion via suppression of JAK2/STAT3 signaling, indicating its potential as a therapeutic target for PPHN and contributing to a more comprehensive understanding of PPHN pathogenesis.