Nobiletin, a hexamethoxyflavone unique to citrus peels, exhibits activity in regulating circadian rhythms. Characterized by a low molecular weight, it can cross the blood-brain barrier and demonstrates various biological functions, including antioxidant, anti-inflammatory, cardiovascular protective, and anticancer effects. However, limitations such as its low water solubility, high crystallinity, and poor stability hinder its nutritional and functional performance in food applications. Therefore, this review summarizes the in vivo absorption of nobiletin, its penetration through the blood-brain barrier, and the biotransformation processes of its active metabolites. Furthermore, this review discusses the regulatory effects on the central clock and peripheral clocks, as well as the mechanisms by which it suppresses related disease progression and promotes overall health via stabilizing circadian rhythms. Moreover, the review summarizes frontier strategies to enhance the stability and bioavailability of nobiletin and identifies the limitations in existing research.