The E3 ligase Nrdp1 has been extensively investigated on cell growth, apoptosis and inflammation in cancer cells and other cell types (Qiu et al., 2004; Wang et al., 2009; Ingalla et al., 2010; Byun et al., 2015). In the present study, we investigated Nrdp1’s role in ischemic neuronal injury. The major findings include: (1) Nrdp1 is significantly upregulated in the ischemic brain tissue and in OGD-treated neuronal cells; (2) overexpression or knockdown of Nrdp1 enhances or attenuates OGD-induced apoptosis in neurons, respectively, and these changes are accompanied by the downregulation or upregulation of Nrdp1’s substrate USP8; and (3) USP8 may directly interact with HIF-1α to prevent its degradation, and under OGD conditions, Nrdp1 may interfere with HIF-1α stabilization via promoting USP8 degradation. These data suggest that Nrdp1 may attenuate neuron’s adaptive response to hypoxia/ischemia via interfering USP8-mediated HIF-1α stabilization, thus contributing to neuronal death under ischemic conditions.