Recently, Escherichia coli (E. coli) exhibited a wide range of antibiotic resistance thus the world is directed to pan the usage of antibiotics and to use antibiotic-safe natural alternatives. Therefore, this study aimed to evaluate the effectiveness of prebiotics and probiotics as a preventive measure to reduce the risk of colibacillosis experimental infection in broiler chicks. 140, one day old broiler chicks were randomly allocated into 7 groups with 20 birds each as follows; groups 1-2 and 3-4 were given prebiotic and prebiotic in drinking water from the 1st to the 5th days of life then at the 6th and 7th days groups 1, 3 and 5, as well as groups 2, 4, and 6 were infected orally each chick with E. coli O78 full drug-sensitive (strain 1) and extreme drug resistance (strain 2), respectively. Groups 5 and 6 were infected with strain 1, and strain 2 infected positives, respectively while group 7 was the control negative group. The results showed that both prebiotic and probiotic have a positive impact on the birds' growth performance, enhance the immune organ weight and histological structure as well as improve the humoral immune response against commercial vaccines, and improve the morphometric structure of the intestinal villi in experimentally infected chickens with two different E. coli O78 strains. In conclusion, it is recommended to use prebiotics and probiotics at the first five days of birds age to reduce the risk of possible E. coli field infection.