Copper is an essential trace element and is required for many metabolic functions. The present study was designed to study the negative impact of excess copper sulphate (Cuso4) on liver of albino rats and studying how its antidote d-penicillamine play role in the development of its side effects. Seventy albino rats were divided into seven equal groups each containing 10 rats (G1:control group received distilled water) ; (G2: 0.1 LD50 of CuSO4) ; (G3: 0.2 LD50 of CuSO4) ; (G4: 0.4 LD50 of CuSO4) ; (G5: 0.1 LD50 of CuSO4 +100 mg/kg/day of penicillamine) ; (G6: LD50 of CuSO4.+100 mg/kg/day of penicillamine) and (G7: LD50 of CuSO4+ 100 mg/kg/day of penicillamine) for 30 days. At the end of the experiment all rats were sacrificed, and blood samples and liver tissues were collected for biochemical and molecular assaying. The result showed that administration of copper sulphate with different levels induced a significant increase in fasting blood glucose level (FBG), lipid peroxidation marker (MDA), serum copper level, white blood cells (WBCs) and serum tyrosinase activity, but a significant decrease in total antioxidant activity (TAC), Hb and platelet count. Moreover, copper sulphate administration elicited a significant (P ˂ 0.05) downregulation of cytochrome c oxidase (Cyto co) and glucose -6- phosphate dehydrogenase (G6PD). It could be approved that d- penicillamine (DPA) can decrease the negative impact of copper sulphate on hepatic tissues and serum enzymes. DPA can reduce hepatotoxicity and oxidative stress caused by copper pollution.