Introduction: Lead exposure remains a significant public health burden across the globe, impacting millions of individuals and posing a major threat to nervous system development and function As a reported bio-toxic environmental and industrial pollutant, Lead (Pb) do accumulates in almost all body tissues to cause health complications with the cerebellar region of the central nervous system reported to be more susceptible to cellular distortions. As a flowering plant species of the Cucurbitaceae family, watermelon (Citrullus lanatus) is associated with numerous medicinal properties. Aim: This study aim to investigate the possible neuroprotective potential of aqueous extract of citrulus lanatus seed on lead acetates-induced neurotoxicity in the Cerebral cortex of adult Wistar rats. Place of Study: Department of Anatomy, Faculty of Basic Medical Sciences Olabisi Onabanjo University, Ogun State, Nigeria. Methods: Twenty (20) healthy adult female wistar rats weighing 150±50g were randomly assigned into 4 groups (n=5). The Control group received 2mls/kg of distilled water, Treatment group (T1) was administered 7.5 mg/kg of lead acetate, Treatment group (T2) was administered 200 mg/kg of aqueous extract of citrullus lanatus and Treatment group (T3) was administered 7.5 mg/kg of lead acetate and 200 mg/kg of aqueous extract of citrullus lanatus concomitantly orally for fourteen (14) days. H&E and Cresyl violet histological stains and Biochemical assays for SOD, CAT activities and MDA concentration was determined. Data obtained from the study were analyzed using one-way ANOVA and subjected to Turkeys post hoc test from the multiple comparison. Results: Revealed no statistically significant differences (p>0.05) in body weight and brain weight changes across groups relatives to the control group while SOD and Catalase activities were increased significantly in the Treatment groups compared to control group. Histological findings in control group and T2 showed normal histoarchitectural appearance of cerebral cortex Pyramidal neurons while the lead exposed group (T1) revealed features of neurodegenerative changes evident by nuclear shrinkage with pyknosis and karryorrhexis. while T3 revealed near normal presentations. Conclusion: In summary, Citrullus lanatus mitigates against pyramidal neuronal cells distortions following lead acetate induced toxicity in Wistar Rats and also further affirms its antioxidative potential.