NADPH plays a key role in mitigating oxidative stress. NADPH provides electrons to the active site of glutathione reductase. Reduction of GSSG back to GSH with free sulfhydryl groups can be used as a direct antioxidant. The NADPH-dependent thioredoxin system also utilizes NADPH. Catalase has a variable binding site for NADPH to maintain itself in an active state. If catalase or glutathione are not effective in scavenging free radicals, the increased H2O2 levels will impede the enzymatic activity of superoxide dismutase. Although catalase and SOD do not directly utilize NADPH for the conversion of H2O2 to water, they still require the assistance of NADPH. In conclusion, NADPH is considered to be the main cellular source of the reducing power of the antioxidant system, and all of these antioxidants ultimately require NADPH for their preservation and fortification. This chapter is aimed to illustrate the functions of NADPH in regulating redox homeostasis.