Hypoxic-ischemic encephalopathy (HIE) is one of the main causes of morbidity and mortality in neonates. On account of high groupings of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrates of antioxidants enzymes, the brain requires elevated degrees of oxygen supply and is, in this manner, very sensitive to hypoxia. Solid proof shows that oxidative stress assumes a significant part in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS) production rapidly increments and overpowers antioxidant defences. A large excess of ROS will straightforwardly change or degenerate cell macromolecules, like membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory reaction, and protease secretion. These derivatives are engaged with a complex interplay of numerous pathways (e.g., inflammation, apoptosis, autophagy, and necrosis) which at last lead to brain injury. In this review, we feature the molecular mechanism for oxidative stress in HIE, sum up current research on therapeutic methodologies used in combating oxidative stress, and attempt to explore novel potential clinical methodologies.