Antioxidant enzymes being an integral part of the defense mechanism have a crucial role in cellular metabolism, essential for healthy growth and living of the cells. The main function is to scavenge and degrade the free radicals, reactive oxygen species (ROS), and reactive nitrogen species (RNS). Endogenous antioxidant enzymes present in mitochondria, cytosol, and other cellular parts participate in capturing and repairing the oxidative damage to the system. Superoxide dismutase, catalase, and glutathione are antioxidant enzymes considered to be part of the first line of defense and are especially important in scavenging reactive oxygen species such as superoxide anion and hydrogen peroxide. Numerous studies in humans, as well as animal models, are correlated and reported about elevation in the enzymatic activity being involved in inhibiting oxidative damage and controlling the disease progression. Similarly, alterations due to enzymatic damage increase oxidative damage and have a key role in disease progression in diseases like cancer, atherosclerotic diseases, neurodegenerative diseases like Parkinson’s, Alzheimer’s, viral diseases, age-related ailments, etc. However, information about antioxidant enzymes, their specificity, free radicals involved in different diseases, and the oxidation process needs to be explored to a greater extent. This review focuses on our current understanding of the role of free radicals and the potential of various antioxidant enzymes, and their great scope in therapeutics against many dreadful diseases.