The circadian clock contributes to the timing of many body functions including metabolism and reproduction. The hepatokine fibroblast growth factor 21 (FGF21) is a critical metabolic regulator involved in modulation of fertility. Here we show that lack of the clock component REV-ERBα elevates FGF21 levels in liver and plasma. At the molecular level, REV-ERBα modulates the expression of FGF21 via the liver-specific hepatic nuclear factor 6 (HNF6). We conclude that REV-ERBα regulates metabolism and reproduction, at least in part, via regulation of Fgf21.