The injury of oligodendrocyte precursor cells (OPCs) contributes to the pathology of hypoxic-ischemic encephalopathy in newborns. MicroRNAs (miRNAs) have emerge as critical regulators of hypoxic-ischemic encephalopathy; however, the role of miRNAs in regulating OPC injury remains largely unknown. MiRNA-146b-5p (miR-146b-5p) has been reported to exert a cytoprotective function under various pathological conditions. In this study, we aimed to investigate the potential function of miR-146b-45p in regulating oxygen/glucose deprivation (OGD)-induced injury of OPCs and explore the underlying mechanism. Herein, we found that miR-146b-5p expression was reduced in OPCs exposed to OGD. Functional experiments showed that miR-146b-5p overexpression promoted cell growth and viability, and reduced the apoptosis and oxidative stress in OGD-injured OPCs, while miR-146b-5p inhibition showed an opposite effect. Interestingly, bromodomain-containing protein 4 (Brd4) was identified as a target gene of miR-146b-5p. Brd4 expression was negatively modulated by miR-146b-5p in OPCs. Moreover, the inhibition of Brd4 showed a protective effect in OGD-injured OPCs. Notably, miR-146b-5p overexpression or Brd4 inhibition down-regulated kelch-like ECH-associated protein 1 (Keap1) expression, but promoted nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear expression and enhanced the transcriptional activity of the antioxidant response element (ARE). However, the overexpression of Brd4 significantly abrogated miR-146b-5p mediated protection effect in OGD exposed OPCs. Taken together, these results demonstrate that the overexpression of miR-146b-5p attenuates OGD-induced injury in OPCs through targeting Brd4 and regulating Keap1/Nrf2/ARE antioxidant signaling, suggesting a potential role of miR-146b-5p/Brd4 in the pathophysiology of neonatal hypoxic-ischemic brain injury.