Demyelinating diseases, such as multiple sclerosis, are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination. Its underlying molecular mechanisms, however, remain unclear The transcription factor prospero homeobox 1 (Proxl) plays an essential role during embryonic development of the central nervous system and cell differentiation. Thus, we aimed to investigate the role of Proxl in the survival and differentiation of oligodendrocytes. Cell viability was measured by MTT assay. Flow cytometry was conducted to analyze cell apoptosis. Ectopic-Proxl and shProxl were used for the overexpression and knockdown respectively of Proxl in FBD-102b cells. Real-time reverse transcriptase polymerase chain reaction and weste blot analysis were used to assess the alterations of signaling pathway-related mRNAs and proteins, respectively. Results showed that Proxl was upregulated in differentiating oligodendrocytes, and Proxl knockdown inhibited the differentiation of oligodendrocytes. In addition, overexpression of Proxl promoted oligodendrocyte differentiation, as shown by the change in myelin basic protein expression. The overexpression of Proxl had no effect on oligodendrocyte survival, while Proxl knockdown impaired cell survival. Further study demonstrated that Proxl knockdown promoted oligodendrocyte apoptosis and activated NOXA, a pro-apoptotic member of the Bcl-2 protein family. Knockdown of NOXA by siRNA abrogated Proxl knockdown-induced apoptosis. Our findings indicated that Proxl regulated the differentiation of oligodendrocyte precursor cells via the regulation of NOXA. Therefore, Proxl could be a potential modulator of demyelinating diseases in clinical settings.