Epigenetic mechanisms are essential in regulating neural progenitor cell self-renewal, with the chromatin-modifying protein Enhancer of zeste homolog 2 (EZH2) emerging as a central player in promoting progenitor cell self-renewal during cortical development. Despite this, howEzh2is itself regulated remains unclear. Here, we demonstrate that the transcription factor nuclear factor IB (NFIB) plays a key role in this process.Nfib^−/−mice exhibit an increased number of proliferative ventricular zone cells that express progenitor cell markers and upregulation of EZH2 expression within the neocortex and hippocampus. NFIB binds to theEzh2promoter and overexpression of NFIB repressesEzh2transcription. Finally, key downstream targets of EZH2-mediated epigenetic repression are misregulated inNfib^−/−mice. Collectively, these results suggest that the downregulation ofEzh2transcription by NFIB is an important component of the process of neural progenitor cell differentiation during cortical development.