This Special Issue explores the role of oxidative stress (OS) in neonatal disorders and potential treatments to help neonates combat OS-related health problems. Basal OS, determined by normal intrauterine hypoxia, is vital for fetal organ development and growth. This may explain why broad-spectrum antioxidant treatments have not been effective in reducing prematurity-related health issues. Conditions such as chorioamnionitis, placental insufficiency, and maternal exposure to reactive oxidative species (ROS) inducers can raise OS levels, increasing the risk of OS-related illnesses in neonates. The perinatal transition, marked by a sudden increase in oxygen levels, also produces large amounts of ROS. When neonates are born prematurely, their immature antioxidant defenses struggle to cope with the surge in oxidative stress. As a result, excessive oxidative stress can lead to conditions such as bronchopulmonary dysplasia, periventricular-intraventricular hemorrhage, necrotizing enterocolitis, retinopathy of prematurity, or periventricular leukomalacia. Furthermore, OS triggers innate inflammation, which further damages immature organs. The cycle of OS and inflammation creates a harmful loop that traditional single-target, single-drug treatments often find hard to control. Animal models have been used to study OS-induced neonatal health issues, and many promising therapies have been explored. However, the limited antioxidative capacity remains a major challenge for researchers. We are still far from finding a cure for OS-related organ damage in premature neonates. New strategies are urgently needed.