Lead nitrate (LN) and cadmium chloride (CdCl2), regarded as environmental contaminants, are toxic heavy metals. Sesamol is a dietary phytochemical found in sesame oil. We aimed to analyze the hepatotoxic and nephrotoxic effects of LN and CdCl2 and to evaluate the possible protective effect of sesamol. LN (90 mg/kg bw per day), CdCl2 (3 mg/kg bw per day), and sesamol (50 mg/kg bw per day) were given to rats via gavage for 28 days. Total protein, albumin, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, total cholesterol, urea, uric acid, creatinine, superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, malondialdehyde, acetylcholinesterase, and histopathological changes were investigated in liver and kidney tissues. Lead and cadmium were found to result in decreases in the antioxidant enzymes and acetylcholinesterase activities, increases in malondialdehyde levels, and changes in serum biochemical parameters and various pathological findings. An improvement in all these parameters was observed in the sesamol-treated groups.