Multidrug resistance transporters (MDRs) are best known for their pathological role in neoplastic evasion of chemotherapeutics and antibiotics. Here we show that MDR-1 is present in the oocyte mitochondrial membrane, and it protects the female gamete from oxidative stress. Female mdr1a mutant mice have no significant difference in ovarian follicular counts and stages, nor in reproductively functioning hormone levels, yet these mice are significantly more vulnerable to gonadotoxic chemotherapy, have chronically elevated reactive oxygen species in immature germinal vesicle oocytes, exhibit a significant over-accumulation of metabolites involved in the tricarboxylic acid cycle (TCA), and have abnormal mitochondrial membrane potential. The mdr1a mutant ovaries have a dramatically different transcriptomic profile with upregulation of genes involved in metabolism. Our findings indicate that functionality of MDR-1 reveals a critical intersection of metabolite regulation, oxidative stress, and mitochondrial dysfunction that has direct implications for human infertility, premature reproductive aging due to oxidative stress, and gonadoprotection.