Niacinamide, a derivative of vitamin B3, and coenzyme Q10 (CoQ10), a component of the electron transport chain, are two molecules with potential benefits for skin health and longevity. This comprehensive review discusses the molecular mechanisms through which niacinamide and CoQ10 contribute to maintaining skin cell vitality and combating inflammatory stressors, both on the skin and within the body. Additionally, it highlights the synergy between these two ingredients in cosmetic formulations and potential interactions with other active ingredients. Evidence suggests that niacinamide and CoQ10 can improve skin barrier function, reduce inflammation, promote collagen synthesis, and mitigate the detrimental effects of ultraviolet radiation. These findings emphasize the importance of niacinamide and CoQ10 in supporting skin health, longevity, and their potential in optimized cosmetic formulations.