Objective: Cigarette smoke is a major reason for inducing reactive oxygen species that result in oxidative damage of testicular tissues and epididymis. This study aimed at investigating the possible protective effect of grape juice on testicular and epididymis damage in rats exposed to cigarette smoke. Methods: Forty adult male rats were used and divided into four groups for this study: control (group Ⅰ), grape juice (group Ⅱ), rats exposed to cigarette smoking (group Ⅲ), and that exposed to cigarette smoking, followed by treatment with grape juice (group Ⅳ). After one month, the rats were weighed and sacrificed. Then, tissues were removed, processed for routine paraffin embedding, stained, and examined for histopathological changes in all groups, and their testosterone levels and antioxidant markers were assessed. The statistical significance among different groups was determined using one-way ANOVA. Results: Histological evaluation of testes showed degenerative alterations, perturbation, and atrophy of spermatogenesis in various seminiferous tubules, along with a reduced number of Leydig cells and less of sperm in epididymis interstitial spaces, as well as reduced activities of antioxidants superoxide dismutase, catalase, and testosterone levels in group Ⅲ than in control groups Ⅰ and Ⅱ. Histopathological changes were reduced while testosterone levels and activities of antioxidants were improved in animals from group Ⅳ. In conclusion, these results may suggest that grape juice has a protective effect against the adverse effects of cigarette smoke in rats via inhibition of oxidative stress and testicular damage.