N-acetylcysteine (NAC) is a derived form of the naturally occurring amino acid L-cysteine. The present work investigated the effect of NAC on Cd and Pb exposed fish. Nile tilapia received NAC supplementations 200 mg/kg fish diet and cultured for 40 days in presence of metals. Fish exposed metals recorded a decrease of growth performance and feed utilization, but NAC reversed the impairment of fish growth performance. Metals also arise WBCs count and decreased HTC and RBCs count, unlike, NAC restored white blood cells count and HTC. Heavy metals also induced deterioration of biochemical parameters (Aspartate aminotransferase “AST", alanine aminotransferase “ALT", alkaline triphosphatase “ALP", urea, triglycerides, total protein “TP", bilirubin, and high-density lipoprotein “HDL"), but NAC succeeded impede this effect through decreasing ALT, AST, ALP, urea and triglycerides values and increased TP levels and HDL. A significant increase of malondialdehyde (MDA) activities and decrease of superoxide dismutase (SOD), glutathione (GSH) and cholinesterase (ChE) were observed in fish exposed to metals, NAC displayed repairing of these antioxidants to levels near to control group. Challenge with metals displayed no fold-change in liver glutathione peroxidase (GPx) gene expression and up-regular effect of liver cytochrome (CYP) gene expression but NAC abolished this effect by achieving the balance of cell proliferation and apoptosis.