Nrf2 is a transcription factor traditionally known to upregulate antioxidant enzymes. In hepatocellular carcinoma, hyperactivation of the Nrf2 pathway is observed in approximately 19% of patients. Nrf2 pathway dysregulation results from activating mutations in Nrf2 or loss of function of the negative regulator of Nrf2, Keap1. Recent evidence suggests that, in addition to regulating the antioxidant response, Nrf2 has a profound impact on cell metabolism. However, the mechanisms underlying this phenomenon are poorly understood. In this study, we have developed complementary in vitro and in vivo models to enable characterization of a Nrf2-driven metabolic reprogramming signature and identify its role in liver cancer. These complementary systems consist of: HepG2 liver cancer cells induced to overexpress clinically relevant Nrf2 mutants; and, a Keap1 knockout zebrafish line generated by CRISPR/Cas9 gene editing. Transcriptomic and metabolomic analysis revealed widespread metabolic reprogramming in both models. Furthermore, we have demonstrated that loss of Keap1 in zebrafish leads to a lethal phenotype that can be rescued with a simultaneous knockout of Nrf2. Interestingly, Keap1 knockout larvae exhibited severe liver abnormalities as the most penetrant phenotype. In conclusion, we have developed powerful systems to examine the role of Nrf2 in liver cancer. Through these systems, we have demonstrated that Nrf2 activation induces metabolic reprogramming in vitro and in vivo, the role of which will be further characterized in our future studies.