The present study was conducted to evaluate the effects of lycopene and vitamin E on hematological parameters, performance, bacterial count and histopathological changes in broiler chicks experimentally infected with E. coli O78. A total of 120 twenty-one-day old chicks were divided into 6 groups. Group (1): was fed on commercial basal diet without any additives. Group (2): was fed on commercial basal diet plus lycopene (200 mg/kg of diet). Group (3): was fed on commercial basal diet plus vitamin E (200 mg/kg of diet). Group ( 4): was fed the commercial basal diet and challenged with E. coli O78 at 3 weeks old. Group ( 5): was fed on commercial basal diet plus lycopene and challenged with E.coli O78 at 3 weeks. Group ( 6): was fed on commercial basal diet plus vitamin E and challenged with E.coli at 3 weeks. Blood samples were taken for assaying hematological changes. Performance parameters were calculated. Samples from lung and intestine were taken under aseptic condition for E. coli count and other parts of these organs were taken on 10% formalin for histopathological examination. Results revealed macrocytic hypochromic anemia, leukocytosis, heterophilia, lymphocytosis and monocytosis in infected non-treated birds. It had poor performance, high liver and intestinal E. coli count and sever histopathological changes in lung and intestine. Treatment with lycopene or vitamin E modulated all of the abovementioned parameters with more improvement in case of lycopene treatment therefore, they partially protect against the destructive effect of E. coli infection.