Fibroblast growth factor 21 (FGF21), an endocrine signal robustly increased by protein restriction, exerts profound effects on feeding behavior and whole-body metabolism. Although the metabolic effects of FGF21 have been widely reported, its role in regulating macronutrient preference is unresolved and controversial. Here, we demonstrate that considering the macronutrient and energy contexts within which FGF21 is elevated helps to reconcile its roles in mediating macronutrient preference, food intake and energy expenditure. In a series of choice experiments, we show that FGF21 is primarily a driver of increased protein intake in mice, and that the effect of FGF21 on sweet preference depends on the carbohydrate balance of the animal. We show that while the role of FGF21 in mediating feeding behavior is complex, its role in promoting protein appetite is robust, leading to selection of protein-rich foods when available, independent of dietary protein background. Effects on sweet preference and energy expenditure are important macronutrient state-dependent consequences of the action of FGF21.