Studies have shown that some drugs impair spermatogenesis, thereby causing infertility. Thus, this study aims at investigating the effect of Persea americana seed extract on the male reproductive system in cyclosporine‐induced rats. Thirty male albino rats were randomly divided into five groups; all groups were induced with cyclosporine except the control group. Group 3 was treated with 10 mg/kg of lisinopril, groups 4 and 5 received 50 and 100 mg/kg of PAE, respectively. The experiment lasted for 7 days. The antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)], and arginase activities were evaluated, nitric oxide (NO) and malondialdehyde (MDA) level of the penile tissue homogenate were determined with serum hormonal (follicle stimulating hormone, luteinizing hormone and testosterone) concentration and sperm quality. This study showed that cyclosporine induction caused a significant (p < .05) decrease in the SOD, CAT, sperm quality, NO, and hormonal level as compared to the control group, with a simultaneous increase in arginase activity and MDA level. However, treatment with PAE and lisinopril significantly (p < .05) increase antioxidant enzyme activities, sperm quality, NO, and serum hormonal level, with a decrease MDA level and arginase activity when compared with cyclosporine‐induced group. This study showed that P. americana seed extract could be useful in the management of hormonal disruption resulting from oxidative stress in male folks. Practical applications Some pharmaco‐agents have been reported to alter spermatogenesis, thereby causing infertility. Plants represent natural resources use in the management of several human diseases from time immemorial. Persea americana seed is a part of the fruit that most people do throw away after consuming the edible portion of the fruit. However, the therapeutic and pharmacological activities of P. americana seed have been reported. Therefore, this study sought to investigate the effects of P. americana seed extract on cyclosporine‐induced reprotoxicity.