Lead (Pb) exposure is considered to be an alarming public health problem since evidence has mounted regarding its adverse impact on health and reproduction. The current research was intended to evaluate the ameliorative effects of Cucurbita pepo L. (pumpkin) against lead toxicity-induced oxidative stress in experimental rats. Before the animal study, a preliminary phytochemical screening was done to detect the presence of various phytoconstituents in the seed extract. Thirty adult male wistar rats were selected and randomly divided into five groups for the experimental study. Group 1 served as the control while groups 2, 3, 4 and 5 were treated with 30 mg/kg lead acetate, 1000 mg/kg seed extract alone (high dose), 30 mg/kg lead acetate and 100 mg/kg seed extract (low dose) and 30 mg/kg lead acetate and 1000 mg/kg seed extract (high dose), respectively. Enzymatic antioxidant concentrations in serum and testis were found to check the response of antioxidants to lead toxicity. In lead treated group, increased oxidative stress was observed which was indicated by a significant (p<0.001) decline in the concentration of the enzymatic antioxidants (SOD, CAT and GPx) coupled with a significant increase in lipid peroxidation marked by high MDA level. Interestingly, at high dosage of C. pepo seed extract, enzymatic antioxidant concentration was comparable to control and significantly higher compared to other experimental groups. The study revealed that even in low dosage, C. pepo administration could improve the antioxidant status in the lead-treated group. This investigation recommends C. pepo seeds as a potent natural product promising strong protection against lead toxicity-induced oxidative stress which could be pharmacologically explored for drug synthesis.