The study of the host immune response of Newcastle disease virus (NDV) infected chickens and the relation between the innate immune response and the intensity of disease during infection in vivo can explain the pathogenesis of NDV. Sixty specific pathogen free (SPF) chickens were divided into four groups. (G1, G2 and G3) were inoculated intra nasally by three different strains of NDV; highly virulent velogenic viscerotropic (VVNDV) (NDV.VII.1.1/Egy-Matr/ELH.5/2018), velogenic neurotropic (VNNDV) (NDV.VII.1.1/Egy-Elbeh/ELH.1/2020) and lentogenic strain (LaSota). The fourth group was used as negative control group. The virus shedding, cytokine measurement, clinical signs, mortality rate, and pathological lesions were compared among these different groups. Our findings revealed that the amount of IFN- α and IFN-γ were increased at 48- and 72-hour post-infection by 2-3 folds in the VVNDV group more than VNNDV group. In addition, the VVNDV group showed higher level of IFN- α and IFN-γ more than LaSota group by 5-6 folds. The course of the disease was severe and rapid 2–4 days in the VVNDV group and much longer 3-6 days in the VNNDV group ending in 100% mortality in both groups but no signs or mortality in the LaSota group. VNNDV group displayed neurological lesions in brain including non-suppurative encephalitis, gliosis, and perivascular cuffing. The three-group infected with velogenic and lentogenic sheded the virus till the 4th day post infection. In conclusion, we found comparative changes in the pathogenesis and cytokine expression in birds infected with velogenic viscerotropic, velogenic neurotropic, and lentogenic NDV strains.