Neonatal calf diarrhea (NCD) is one of the most serious diseases affecting dairy herds in many parts of the world. This disease leads to high morbidity and mortality causing significant economic losses. This study was aimed to determine the incidence of Bovine Rotavirus (BRV) and Enterotoxigenic E.coli (ETEC) in new born calves in Egypt to understand the consequences of these pathogens on the immune status and the biochemical alterations related to these infections. Out of 100 sampled diarrheic calves, 8% were positive for BRV, with 6% of them having ETEC co-infection. In E. coli isolates, resistance genes like blaTEM and qnrA showed spread of multidrug resistance. Calves suffering from the infection were found to have considerably lowered immunoglobulins (IgG, IgM, IgA), but had raised levels of lysozyme and Nitric oxide especially in the co-infected group. There was also an electrolyte imbalance, increased serum proteins and elevated values of pro-inflammatory cytokines (IL1 β, IL6 and TNF α). These results highlight the immune antagonism and systemic inflammation that is a feature of BRV and ETEC co-infections in NCD indicating a potential need to change antimicrobial strategies, include better diagnostic techniques to control the spread of the infections and enhance the health of the calves .