In recent times, there has been a renewed interest in mushrooms owing to their rich bioactive compounds with the capacity to neutralize oxidative damage. The present review assesses the promise of mushrooms in supporting the defense mechanisms of the body against oxidative stress through a critical consideration of their chemical composition, bioactivities, and evidence from both in vitro and in vivo studies. Mushrooms are evidenced in a variety of antioxidants such as phenolic acids, flavonoids, and β-glucans, as well as essential vitamins like B-complex vitamins and vitamin E, as well as trace minerals like selenium and zinc. In addition, mushrooms also exhibit unique antioxidants such as ergothioneine and glutathione. Altogether, the above elements operate synergistically to chelate toxic metal ions, scavenge free radicals, as well as block lipid peroxidation, thus protecting cellular integrity. One of the mechanisms by which fungi reduce oxidative stress is by the action of their compounds to modulate the Keap1/Nrf2/ARE pathway, a regulatory circuit essential for the manufacture of the body’s protective enzymes. Efficient action of the pathway is critical to maintaining redox balance. Interesting medicinal mushrooms such as Ganoderma lucidum (Reishi), Lentinula edodes (Shiitake), Cordyceps militaris, and Hericium erinaceus (Lion’s Mane) have shown considerable antioxidant, neuroprotective, immunomodulatory, as well as anti-inflammatory activities, attested by both in vitro experiments as well as clinical trials. All the fungi that have so far been studied have proved to reduce markers for oxidative stress, including malondialdehyde (MDA), while increasing the activity of endogenous antioxidant enzymes like superoxide dismutase (SOD) and catalase. Various assays like DPPH, ABTS, and FRAP have provided corroborative evidence supporting the strong antioxidant activity of mushroom extracts. Animal as well as human studies further validate evidence by proving the increase in oxidative balance and protection against diabetes, cardiovascular disorders, and neurodegenerative disorders. However, various factors need to be further investigated. The level of beneficial compounds present in the mushrooms can vary as a function of the particular species of mushroom used, the production process used, and handling procedures used, and hence, the results can vary. Therefore, the standardization of extraction techniques and tight quality control measures is a must. Furthermore, because of the disparity in the regulatory frameworks of different countries, the regulation and approval of the mushroom supplements pose an additional hurdle. Despite all the above, the visibility of the mushroom antioxidants is increasing in the health and well-being industries—especially in functional foods, dietary supplements, and products used for cosmetics. Reishi capsules and Lion’s Mane teas are increasingly becoming popular and show promise as new findings are made. Nonetheless, large and stringently controlled studies are still needed to firmly establish their health advantages as well as their optimal dosages. Overall, fungi are a renewable and accessible resource for natural antioxidants with great promise for health promotion and prevention of disease. Ongoing research into their bioactive compounds and mechanisms will be crucial for the complete realization of their therapeutic actions.