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Neural progenitor cells (NPCs) therapy, a promising therapeutic strategy for neurodegenerative diseases, has a huge challenge to ensure high survival rate and neuronal differentiation rate. Cerium oxide (CeO2) nanoparticles exhibit multienzyme mimetic activities and have shown the capability of regulating reactive oxygen species (ROS), which is a pivotal mediator for intracellular redox homeostasis in NPCs, regulating biological processes including differentiation, proliferation, and apoptosis. In the present study, the role of facet-dependent CeO2-mediated redox homeostasis in regulating self-renewal and differentiation of NPCs is reported for the first time. The cube-, rod-, and octahedron-shaped CeO2 nanozymes with different facets are prepared. Among the mentioned nanozymes, the cube enclosed by the (100) facet exhibits the highest CAT-like activity, causing it to provide superior protection to NPCs from oxidative stress induced by H2O2; meanwhile, the octahedron enclosed by the (111) facet with the lowest CAT-like activity induces the most ROS production in ReNcell CX cells, which promotes neuronal differentiation by activated AKT/GSK-3 beta/beta-catenin pathways. A further mechanistic study indicated that the electron density of the surface Ce atoms changed continuously with different crystal facets, which led to their different CAT-like activity and modulation of redox homeostasis in NPCs. Altogether, the different surface chemistry and atomic architecture of active sites on CeO2 exert modulation of redox homeostasis and the fate of NPCs.