The applications of natural products in aquaculture to improve fish production and modulate toxic undesired effects of heavy metals represent a global environmental demand. In this study, fish diets supplemented with natural zeolite (Clinoptilolite) were evaluated for their ability to improve growth and alleviate the deleterious effects of lead acetate in Nile tilapia (Oreochromis niloticus). Four main experimental groups were used: one control group that fed on diets supplemented with 0% zeolite and three treatment groups received 1%, 3% and 5% zeolite. After 45 days of feeding, zeolite treatments resulted in a positive effect on weight gain (WG) with a significant reduction in water ammonia levels. Following feeding experiment, the control group was divided into two groups. All zeolite-treated groups and one of the control groups (Control +ve) were subjected to lead (Pb) toxicity for additional 21 days, while the other control received no Pb (Control –ve). Exposure to Pb significantly decreased protein and albumin on one hand and increased glucose, cholesterol, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) on the other. Elevation of hepatic catalase (CAT), superoxide dismutase (SOD) and total antioxidant capacity (TAC) were also detected. In contrast, zeolite feeding before and during Pb exposure showed an increase in protein and albumin levels, and a decrease in glucose, cholesterol, ALT, AST, CAT, SOD and TAC levels. Moreover, zeolite decreased Pb residues in muscles and increased it in kidneys. All in all, the data presented indicate that zeolite can improve the growth performance in Nile tilapia and increases fish resistance to undesired effects associated with Pb toxicity.