This study was conducted on 250 Cobb broilers, healthy chicks one- day- old, to evaluate and compare the impact of using water natural additives (such as acidifier and probiotics) on broiler. Complete blood pictures and immune response, as well as histopathological in treated and experimentally infected chickens with E.coli compared to control.The birds were randomly allotted to ten treatment groups (A - J). Control, probiotic (HerriC 20%) as 0.5 gm, 1gm / 4 liters of drinking water respectively, acidifier (AniGut) as at dose of 1 and 2 ml/ litre of drinking water respectively and another same treatment groups and infected with E coli O78 containing 4 x 10⁶ colony-forming units CFU /ml in phosphate buffered saline (PBS) at 21 days of age. The result indicated that, probiotic treated groups ‘showed significant increase (P<0.05) in RBCs count and PCV value at 4 and 6 weeks, showed non-significant changes in Hb conc., MCV, MCH and MCHC in compare with the control, while acidifier treated groups showed non-significant changes in erythrogram. The leukogram studies revealed that, there was increase in TLC with characteristic heterophilia, lymphocytosis, and monocytosis in infected non treated group and in probiotic treated groups, while acidifier treated groups showed non-significant changes in TLC and D.L.C all over the experiment. The result of immunological parameters showed an elevation in the serum of IgG and IgM in infected group and in probiotic treated groups. While acidifier treated groups showed non-significant changes. The results of IL-6 and IL-12 showed that there were a significant increase in all infected groups and in probiotic treated groups, while acidifier treated groups showed non-significant changes. Histopathological results showed that addition of probiotic improved all the examined organs. The study concluded that Probiotic has marked growth promoter as well as immunomodulatory effects in broilers, the low dose of probiotic (0.5 gm) proved to be more beneficial than the higher dose.