The ketone bodies, especially β-hydroxybutyrate (β-HB), derive from fatty acid oxidation and alternatively serve as a fuel source for peripheral tissues including the brain, heart, and skeletal muscle. β-HB is currently considered not solely an energy substrate for maintaining metabolic homeostasis but also acts as a signaling molecule of modulating lipolysis, oxidative stress, and neuroprotection. Besides, it serves as an epigenetic regulator in terms of histone methylation, acetylation, β-hydroxybutyrylation to delay various age-related diseases. In addition, studies support endogenous β-HB administration or exogenous supplementation as effective strategies to induce a metabolic state of nutritional ketosis. The purpose of this review article is to provide an overview of β-HB metabolism and its relationship and application in age-related diseases. Future studies are needed to reveal whether β-HB has the potential to serve as adjunctive nutritional therapy for aging.