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Chronic exposure to heavy metals poses severe health risks. This study investigates the protective effects of zinc and selenium against nephrotoxicity, antioxidant and anti/proinflammatory effects induced by lead and cadmium in male Wistar rats exposed to Pb and Cd in their drinking water. Thirty male Wistar rats were divided into five groups, a control group, a group exposed to Pb and Cd, a group treated with Zn and Se plus Pb and Cd, two other groups administered Zinc at 1 mg/kg and and Selenium at 1.5 mg/kg with Pb and Cd respectively. The rats were exposed to Pb and Cd for 90 days, after which blood and kidneys were collected for analysis. Results showed that lead and cadmium exposure significantly increased heavy metal accumulation in blood and kidneys, reduced antioxidant enzyme activity (SOD, catalase, GSH), and increase lipid peroxidation (MDA). Results showed that lead and cadmium exposure significantly increased lipid peroxidation, elevated pro-inflammatory cytokines, and reduced antioxidant enzyme activity. However, supplementation with zinc and selenium improved antioxidant defenses, reduced inflammation, and mitigated renal toxicity. These findings suggest that zinc and selenium supplementation may serve as potential therapeutic agents against heavy metal-induced nephrotoxicity.