SignificanceThe KEAP1–NRF2 pathway plays a central role in the regulation of redox balance and cellular metabolism. Although NRF2 has been extensively investigated in various disease states, including cancer, there is a paucity of knowledge regarding the role of NRF2 during embryonic development. Here, we demonstrate that NRF2 activation induces lethality that is preceded by liver abnormalities and accumulation of lysosomes. Moreover, we find that NRF2 activates the master regulators of lysosomal biogenesis, TFEB/TFE3. These studies highlight a critical role for the maintenance of lysosomal homeostasis during embryonic development and, more broadly, suggest that aberrant lysosomal biogenesis may be a hallmark of NRF2-driven pathologies.