Background <p>Infertility is a serious clinical condition that may have numerous causes; one of the most common causes of female infertility is chemotherapeutic-induced reduction of ovarian function and follicular count, which may lead to early menopause. This is known clinically as premature ovarian insufficiency (POI).</p> Materials and method <p>Fifty female albino rats <i>(Rattus norvegicus)</i> were divided into five groups. Group I received no treatment, and then POI was generated in all the remaining groups by intraperitoneal injections of 50 mg/kg of cyclophosphamide on the first day, followed by 8 mg/kg for 15 consecutive days. Subsequently, group II (cyclophosphamide group) was left untreated, whereas group III was administered a volume of 100 µL exosome (1 mL PBS containing 1 × 10¹⁰ particles of ovarian stem cell-derived exosome) via intraperitoneal injection twice weekly for a month. Group IV was administered 1 mL of phosphate-buffered saline containing 1 × 10⁶ adipose-derived stem cells through intraperitoneal injection once weekly for 1 month. Group V received a combined treatment (ovarian stem cell-derived exosomes and adipose stem cells). Thirty days post-POI induction, the rats were euthanized, and blood was drawn to assess hormone levels. Sections of ovarian tissue were stained by Hematoxylin and Eosin (H&amp;E) and immunohistochemical staining for Proliferating Cell Nuclear Antigen (PCNA) and caspase 3. Additionally, gene expression and oxidative stress were analyzed.</p> Results <p>The cyclophosphamide group had an elevated follicle-stimulating hormone (FSH) and reduced estrogen (E2) levels when compared to the control and treatment groups. Additionally, the Cyclophosphamide (CLP) group ovaries exhibited desquamation of granulosa cells and degeneration of ovarian follicles. Gene expression indicated that AMH, CYP19A1, and FSHR were all downregulated in the CLP group. The rats treated with ovarian stem cells (OSCs) derived exosomes, adipose-derived stem cells (ADMSCs), and the mix group exhibited a decrease in granulosa cell apoptosis, a rise in serum E2 levels, a decrease in serum FSH levels, an up-regulation of the three assessed genes, and a reduction in oxidative stress parameters.</p> Aim of work <p>The study aimed to evaluate the therapeutic effectiveness of ovarian stem cells-derived exosomes, adipose-derived stem cells and their combination in repairing POI induced by cyclophosphamide.</p> Conclusion <p>Treatment with OSC-derived exosomes and ADMSCs enhanced the structure and function of the ovaries, thereby alleviating the adverse effects of cyclophosphamide.</p>