Medicinal mushrooms, as a rich source of health-promoting compounds, have been at the center of much research over the last decades. Immunomodulatory, antioxidant activity, antitumor, neuroprotection, and antiaging effects are among the important attributes of these mushrooms. Their significant results on health are due to various types of components, especially bioactive compounds, including polysaccharides, ergothioneine, polyphenols, flavonoids, carotenoids, lectins, and terpenoids, which make their impact through different molecular basis and mechanisms of action. The antioxidant activity of these compounds is exerted by both direct and indirect antioxidant pathways. Direct pathways are carried out via scavenging reactive oxygen species and chelating of pro-oxidant metals, preventing Fenton reactions and cellular damage. In indirect pathways, they modulate endogenous antioxidant defenses by upregulating essential antioxidant enzymes. This chapter aims to provide an inclusive review of molecular mechanisms of medicinal mushrooms’ components, in which they exhibit beneficial impacts on health, especially their antioxidant activity.