Objective To investigate the role and mechanism of miR-146b-5p in pulmonary vascular remodeling in neonatal rats with bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) induced by hyperoxia. Methods Thirty-two Sprague-Dawley neonatal rats were randomly assigned to normoxia group, BPD-PH group, overexpression group, and inhibitor group (n=8 per group). The normoxia group was raised in 21% oxygen, while the other groups were exposed to 85.0%±0.5% hyperoxia to induce BPD-PH. The overexpression group received tail vein injection of ADV1-miR-146b-5p adenovirus; the inhibitor group received miR-146b-5p inhibitor injections. After 14 days, adenovirus transfection efficiency in lung tissue was confirmed by confocal microscopy. Right ventricular systolic pressure (RVSP) was measured by direct manometry. Right ventricular hypertrophy index (RVHI) was calculated by weighing isolated ventricular tissues. Hematoxylin-eosin staining was used to assess pulmonary vascular morphology, and medial thickness percentage (MT%) and medial area percentage (MA%) of pulmonary vessels were calculated. Mitochondrial ultrastructure of pulmonary vascular endothelial cells was observed by transmission electron microscopy (TEM). Iron deposition in lung tissue was detected by DAB Prussian blue staining and ferrous ion colorimetric assay. Quantitative real-time PCR was used to measure mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and acyl-CoA synthetase long-chain family member 4 (ACSL4). Protein expression levels of these molecules were detected by Western blotting. Results Compared with the normoxia group, the BPD-PH group showed significantly increased RVSP, RVHI, MT%, and MA% (P<0.05), swollen mitochondria, increased iron deposition, downregulated mRNA and protein expression of Nrf2, GPX4, and SLC7A11, and upregulated expression of ACSL4 (P<0.05). Compared with the BPD-PH group, the overexpression group exhibited further increases in RVSP, RVHI, MT%, and MA%, severe mitochondrial swelling, significantly elevated iron deposition, decreased Nrf2, GPX4, and SLC7A11 mRNA and protein levels, and increased ACSL4 expression (P<0.05). In contrast, the inhibitor group demonstrated decreased RVSP, RVHI, MT%, and MA%, alleviated mitochondrial swelling, reduced iron deposition, upregulated mRNA and protein levels of Nrf2, GPX4, and SLC7A11, and downregulated mRNA and protein levels of ACSL4 (P<0.05). Conclusions Overexpression of miR-146b-5p promotes pulmonary vascular remodeling in neonatal rats exposed to hyperoxia, likely through inhibition of the Nrf2/GPX4 signaling pathway and regulation of ferroptosis.