The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high-fat diet, including the development of obesity and insulin resistance. These metabolic adaptations involve altered liver function. Here, we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα). Therefore, JNK causes decreased expression of PPARα target genes that increase fatty acid oxidation and ketogenesis and promote the development of insulin resistance. We show that the PPARα target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPARα-FGF21 hormone axis suppresses the metabolic effects of JNK deficiency. This analysis identifies the hepatokine FGF21 as a critical mediator of JNK signaling in the liver. Display omitted •The PPARα-FGF21 hormone axis promotes insulin sensitivity•Consumption of a high-fat diet activates JNK in the liver•Hepatic JNK represses PPARα and contributes to systemic insulin resistance Consumption of a high-fat diet activates the protein kinases JNK1/JNK2 in the liver. Vernia et al. identify the PPARα-FGF21 axis as a key target for hepatic JNK signaling to promote systemic insulin resistance.