Lead  (Pb) contamination, caused by human activities, is a prevalent issue in aquatic environment and poses significant risks to fish and human health. Fish, in particular, are highly susceptible to lead accumulation, impeding their growth and overall well-being. This experiment inspected the adverse impacts of lead acetate toxicity on various aspects of Nile tilapia's health, water quality, fish muscle quality, and gene expression. The study also investigated the potential mitigating effects of dietary inclusion with pomegranate pulp. One hundred twenty healthy Nile tilapia of similar sizes were randomly split into four experimental groups: a control group, a group supplemented with pomegranate pulp at 15%, a group exposed to lead acetate 24.4 mg/L (20% of the LC50), and a group exposed to both pomegranate pulp and lead acetate. The fish were fed their respective diets for six weeks, and various parameters were assessed. The findings revealed that lead acetate exposure significantly hindered fish growth and resulted in increased stress biomarkers, leading to liver damage and renal failure. Furthermore, lead acetate negatively affected immune parameters and caused elevated oxidative stress levels in the liver and kidneys. However, inclusion pomegranate pulp effectively alleviated these adverse effects by enhancing antioxidant and immune activities. The study also demonstrated that pomegranate inclusion reduced muscle damage and improved the quality of fish meat. Additionally, it influenced the genes expression associated with antioxidant activity, apoptosis, and detoxification in various organs of Nile tilapia. In conclusion, lead acetate had detrimental consequences on the performance of Nile tilapia, but dietary inclusion with pomegranate pulp proved to be an effective strategy for mitigating these effects. Pomegranate pulp enhances antioxidant defenses, boosts immune response, and improves overall health, thereby reducing the adverse impacts of lead exposure.