In this study, we explored the mechanism of bixin in the activation of Nrf2 signals and demonstrated that activation of Nrf2 by bixin suppressed the NF-κB pathway and upregulated the PPARα with its targets, which plays a pivotal role in hepatic steatosis and inflammation by using a high-fat diet- (HFD-) fed mice model. This evidence concerns the gene PPARA and fatty liver disease.