The circadian clock is the biological mastermind governing orderly execution of bodily processes throughout the day. In recent years, an emerging topic of broad interest is clock-modulatory agents, including small molecules both of synthetic and natural origins, and their potential applications in disease models. Nobiletin is a naturally occurring flavonoid with the greatest abundance found in citrus peels. Extensive research has shown that Nobiletin is endowed with a wide range of biological activities, yet its mechanism of action remains unclear. We recently found through unbiased chemical screening that Nobiletin impinges on the clock machinery to activate temporal control of downstream processes within the cell and throughout the body. Using animal models of diseases and aging, we and others illustrate potent beneficial effects of Nobiletin on cellular energetics in both periphery and brain to promote healthy aging. Given its excellent safety profile, Nobiletin may represent a promising candidate molecule for development of nutraceutical and chronotherapeutic agents against chronic and age-related neurodegenerative diseases.