INTRODUCTION: Hyperoxic lung injury results from excessive supplemental oxygen therapy in conditions such as bronchopulmonary dysplasia (BPD) in preterm infants and acute respiratory distress syndrome (ARDS) in adults. This review explores the role of cytochrome P450 reductase (CPR) in hyperoxic lung injury. AREAS COVERED: Hyperoxia induces the production of reactive oxygen species in excessive amounts, overwhelming the body's antioxidant defenses and exacerbating lung injury in ARDS/BPD. This review examines the differential roles of CPR-dependent enzymes in the context of hyperoxic lung injury. Additionally, we highlight the potential of targeting CPR to study mechanisms of lung injury and leverage gene-editing technologies to deepen our understanding of CPR-mediated pathways. This review consolidates existing knowledge on CPR-dependent processes and their roles in hyperoxic lung injury, based on a literature search conducted in the PubMed database for studies published between 1988 and 2024. EXPERT OPINION: This review emphasizes the need for a deeper understanding of disease mechanisms, particularly CPR-mediated pathways. As a regulatory hub for ROS modulation and enzyme activity, CPR represents a promising target, offering a unified strategy to mitigate hyperoxic lung injury and improve outcomes in BPD/ARDS.