This study investigated the clinical and pathological symptoms of waterborne lead toxicity in wild Nile tilapia collected from a lead-contaminated area (the Mariotteya Canal: Pb = 0.6 ± 0.21 mg L−1) and a farmed fish after 2 weeks of experimental exposure to lead acetate (5–10 mg L−1) in addition to evaluating the efficacy of neem leaf powder (NLP) treatment in mitigating symptoms of lead toxicity. A total of 150 fish (20 ± 2 g) were alienated into five groups (30 fish/group with three replicates). G1 was assigned as a negative control without any treatments. Groups (2–5) were exposed to lead acetate for 2 weeks at a concentration of 5 mg L−1(G2 and G3) or 10 mg L−1(G4 and G5). During the lead exposure period, all groups were reared under the same conditions, while G3 and G5 were treated with 1 g L−1NLP. Lead toxicity induced DNA fragmentation and lipid peroxidation and decreased the level of glutathione and expression of heme synthesis enzyme delta aminolaevulinic acid dehydratase (ALA-D) in wild tilapia, G2, and G4. NLP could alleviate the oxidative stress stimulated by lead in G3 and showed an insignificant effect in G5. The pathological findings, including epithelial hyperplasia in the gills, edema in the gills and muscles, degeneration and necrosis in the liver and muscle, and leukocytic infiltration in all organs, were directly correlated with lead concentration. Thus, the aqueous application of NLP at 1 g L−1reduced oxidative stress and lowered the pathological alterations induced by lead toxicity.