Elimination of oxidized proteins is important to cells as accumulation of damaged proteins causes cellular dysfunction, disease, and aging. Abundant evidence shows that the 20 S proteasome is largely responsible for degradation of oxidative proteins in both ubiquitin-dependent and ubiquitin-independent pathways. However, the role of the REGγ–proteasome in degrading oxidative proteins remains unclear. Here, we focus on two of the well-known REGγ–proteasome substrates, p21^Waf1/Cip1 and hepatitis C virus (HCV) core protein, to analyze the impact of oxidative stress on REGγ–proteasome functions. We demonstrate that REGγ–proteasome is essential for oxidative stress-induced rapid degradation of p21 and HCV proteins. Silencing REGγ abrogated this response in multiple cell lines. Furthermore, pretreatment with proteasome inhibitor MG132 completely blunted oxidant-induced p21 degradation, indicating a proteasome-dependent action. Cellular oxidation promoted REGγ–proteasome-dependent trypsin-like activity by enhancing the interaction between REGγ and 20 S proteasome. Antioxidant could counteract oxidation-induced protein degradation, indicating that REGγ–proteasome activity may be regulated by redox state. This study provides further insights into the actions of a unique proteasome pathway in response to an oxidative stress environment, implying a novel molecular basis for REGγ–proteasome functions in antioxidation.