Low-quality oocytes directly affect fertilization and embryonic development, contributing to infertility in women, while germ cell senescence leads to reduced germ cell numbers and decreased egg quality. Dasatinib and quercetin (D and Q), as senolytic drugs, have been extensively explored in different age-related diseases. However, their effects on in vitro cultured senescent oocytes and the molecular mechanisms underpinning ovarian aging remain elusive. Here, we report that a nano-encapsulated senolytic D + Q cocktail efficiently improves the quality of post-ovulatory aging oocyte in vitro and follicle quantity in ovaries in a cyclophosphamide (Cy)-induced premature ovarian failure (POF) mouse model. Cocktail supplementation to cultured oocytes potently reduces reactive oxygen species (ROS) levels, maintains spindle integrity, decreases fragmented oocyte frequencies, rescues mislocalized cortical granules (CGs) and mitochondrial membrane potential (MMP), and alleviates DNA damage and apoptosis. Importantly, the cocktail effectively ameliorates fertility deficits in the model. Transcriptome analysis shows cocktail administration to fertility-deficient mice not only up-regulates developmental gene expression but also reduces senescence-associated secretory phenotype (SASP) accumulation. Therefore, our nano-encapsulated D + Q cocktail is a promising reagent for assisted reproductive technology and improving reproductive outcomes in POF.