Background: Lead is the most ubiquitous hazardous toxin in the environment. It’s a severe threat to public health, especially in the male reproductive system. Vitis vinifera seeds (grape seeds) are natural, rich sources of antioxidant compounds. Aim: The present study was undertaken to investigate the effect of Vitis vinifera seed extract against the deterioration of antioxidant enzymes and testicular histomorphological changes caused by lead acetate. 24 male Wistar rats were used for the study and were divided into Group I: control (6 rats) and Group II: the remaining 18 rats were administered with LA (lead acetate) 50 mg/kg BW for 28 days; at the end of the 28th day, all 18 rats were divided equally into three groups: Group II (a): lead acetate ceased; Group II (b): rats treated with GSE (grape seed extract) 200 mg/kg BW; and Group II (c): rats treated with GSE 400 mg/kg BW orally once a day from the 29th to the 56th day. At the end of 56 days, levels of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in testicular tissue were measured in rats. Testis tissue samples were also collected for histological studies. Results and conclusion: The current study showed that in comparison to control rats, LA-ceased group showed significantly elevated lipid peroxidation, as evidenced by a large rise in MDA levels and a significantly reduced level of the antioxidant enzymes SOD, CAT, GPx, and reduced glutathione (GSH). Additionally, severe histomorphological alternations were observed in LA-ceased rats. The post-treatment effect of grape seed extract significantly reversed the effect of lead acetate with the restoration of oxidative stress markers and the histoarchitecture of the testes. It is also a powerful natural antioxidant that shows promise as a treatment for rats with testicular injuries caused by lead acetate.