Cyclophosphamide is used to treat various types of cancer. However, it can reduce ovarian function and fertility rate. The current study was done to compare the effects of N-acetylcysteine and vitamin E on cyclophosphamide-induced ovarian damage. Thirty-five rats were randomly divided into 5 groups: control (C), cyclophosphamide (CP, 200 mg/kg single dose intraperitoneally), T1 (cyclophosphamide + vitamin E at 200 mg/kg), T2 (cyclophosphamide + 200 mg/kg N-acetylcysteine), and T3 (cyclophosphamide + N-acetylcysteine and vitamin E at 200 mg/kg). The main measurements included total antioxidant capacity (TAC), glutathione peroxidase (GPx), malondialdehyde (MDA), interleukin 8 (IL-8), tumor necrosis factor-α (TNFα), follicle stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (ES). Except for the C and T3 groups, the other groups lost weight. A significantly lower concentration of MDA was observed in the T3 group. However, TAC was substantially increased compared to the other groups. The level of GPx in the S group was significantly reduced compared to all groups. Proinflammatory markers (IL-8 and TNFα) reached their lowest serum level in the T3 group, with a statistically significant difference compared to that of the S group. In addition, there were no significant differences in the means of primary, secondary, and graph and atretic follicles between the T3 and C group. On the other hand, a decrease in FSH and LH was observed while an increase in ES was seen in the T3 group compared to the S group. This study revealed that N-acetylcysteine and vitamin E coadministration could significantly decrease the side effects of cyclophosphamide, especially in ovarian tissue.