Obesity, a significant health crisis, arises from an imbalance between energy intake and expenditure. Enhancing appetite regulation has garnered substantial attention from researchers as a novel and effective strategy for weight management. The melanocortin system, situated in the hypothalamus, is recognized as a critical node in the regulation of appetite. It integrates long-term and short-term hormone signals from the periphery as well as nutrients, forming a complex network of interacting feedback mechanisms with the gut-brain axis, significantly contributing to the regulation of energy homeostasis. Appetite regulation by bioactive compounds has been a focus of intensive research due to their favorable safety profiles and easy accessibility. These bioactive compounds, derived from a variety of plant and animal sources, modulate the melanocortin system and influence appetite and energy homeostasis through multiple pathways: central nervous system, peripheral hormones, and intestinal microbiota. Here, we review the anatomy, function, and receptors of the melanocortin system, outline the long-term and short-term regulatory hormones that act on the melanocortin system, and discuss the bioactive compounds and their mechanisms of action that exert a regulatory effect on appetite by targeting the melanocortin system. This review contributes to a better understanding of how bioactive compounds regulate appetite via the melanocortin system, thereby providing nutritional references for citizens' dietary preferences.