An increase in oxidative protein damage is a leading contributor to age-associated decline in oocyte quality. Through the removal of such damaged and / or dysfunctional proteins, the proteasome plays an essential role in maintaining the fidelity of oocyte meiosis. Our study reveals a decrease in proteasome activity in the naturally aged germinal vesicle (GV) mouse oocyte that is positively correlated with increased protein modification by the lipid aldehyde, 4-hydroxynonenal (4-HNE). This highly reactive lipid aldehyde, generated as a by-product of lipid peroxidation cascades, can covalently adduct and dysregulate the function of key oocyte proteins including α-tubulin, a structural component of the oocyte’s meiotic spindle; thus, contributing to a reduction in the integrity of oocyte meiosis. Further, we have shown that inhibition of proteasome activity (MG132; 50 μM) in oxidatively stressed GV oocytes obtained from young animals leads to an attendant increase in the accumulation of 4-HNE-modified proteins, including α-tubulin. Among alternative protein targets for 4-HNE adduction, we identified several subunits of the proteasome as being particularly vulnerable. Accordingly, proteasomal activity was also significantly attenuated in a dose-dependent manner in young oocytes exposed to an acute oxidative insult (H2O2 or 4-HNE). Notably, the inclusion of the antioxidant, penicillamine, to limit propagation of oxidative stress cascades led to a complete recovery of proteasome activity and enhanced clearance of 4-HNE adducted α-tubulin during a 6 h post-H2O2 treatment recovery period. This strategy also proved effective in reducing the incidence of oxidative stress-induced aneuploidy following in vitro oocyte maturation. Taken together, our data implicates proteasome dysfunction as an important factor in the accumulation of oxidatively induced damage in the female germline.