Lead (Pb) toxicity is one of the most common causes of human cardiotoxicity. We evaluated the therapeutic role of Solanum nigrum extract (SNE) and dithiophenolate-chitosan nanoparticle (DTP-CSNP) on Pb-induced cardiotoxicity in rats, and the results were compared with the dimercaptosuccinic acid (DMSA, reference drug). Additionally, the combination effect of SNE and DTP-CSNP against Pb-induced cardiotoxicity was assessed. The study focused on the determination of the antioxidant, anti-inflammatory, anti-apoptotic, and cardiotherapeutic functions of SNE (375 mg/kg), DTP-CSNP (20 and 40 mg/kg), and their combination (SNE + DTP