Acetaminophen (N‐acetyl‐para‐aminophenol [APAP]) overdose is the most common cause of drug‐induced liver injury in the Western world and has limited therapeutic options. As an important dietary component intake, fructose is mainly metabolized in liver, but its impact on APAP‐induced liver injury is not well established. We aimed to examine whether fructose supplementation could protect against APAP‐induced hepatotoxicity and to determine potential fructose‐sensitive intracellular mediators. We found that both high‐fructose diet feeding before APAP injection and fructose gavage after APAP injection reduced APAP‐induced liver injury with a concomitant induction of the hepatic carbohydrate‐response element‐binding protein α (ChREBPα)–fibroblast growth factor 21 (FGF21) pathway. In contrast, Chrebpα liver‐specific‐knockout (Chrebpα‐LKO) mice failed to respond to fructose following APAP overdose, suggesting that ChREBPα is the essential intracellular mediator of fructose‐induced hepatoprotective action. Primary mouse hepatocytes with deletion of Fgf21 also failed to show fructose protection against APAP hepatotoxicity. Furthermore, overexpression of FGF21 in the liver was sufficient to reverse liver toxicity in APAP‐injected Chrebpα‐LKO mice. Conclusion: Fructose protects against APAP‐induced hepatotoxicity likely through its ability to activate the hepatocyte ChREBPα–FGF21 axis.