Nanomaterials with enzyme-like activity, generally referred to as ‘nanozymes’, find myriad potential in various biomedical fields. More importantly, the nanoparticles that can functionally mimic the activity of cellular antioxidant enzymes attract tremendous interest owing to their possible therapeutic candidature in oxidative stress-mediated disorders. Oxidative stress culminating due to excess reactive oxygen species (ROS) level and dysregulated cellular antioxidant machinery is implicated in the development and progression of various pathophysiological disorders such as cancer, diabetes, cardiovascular and neurodegenerative diseases. Moreover, the optimum essentiality of ROS due to its pivotal role in cell signaling evokes the requirement of novel artificial antioxidant enzymes that can circumvent the detrimental effects of enhanced ROS levels without perturbing the basal redox status of cells. In recent years, the fast emanating artificial enzymes, i.e. nanozymes with antioxidant enzyme-like activity, has made tremendous progress with their broad applications in therapeutics, diagnostic medicine, bio-sensing, and immunoassay. Among various antioxidant nanoparticles reported till-date, the metal oxide nanozymes have emerged as the most efficient and successful candidates in mimicking the activity of first-line defense antioxidant enzymes, i.e. superoxide dismutase, catalase, and glutathione peroxidase. This review intends to exclusively highlight the development of representative metal oxide-based antioxidant nanozymes capable of maintaining the cellular redox homeostasis and their potential therapeutic significance.