This study aimed at evaluating the immunological status of Oreochromis niloticus (O. niloticus); so, a total of 120 O. niloticus were collected from different farms located in Kafr El-Sheikh Governorate in Egypt during the period from January 2021 to January 2022. The fish were surveyed for commonly encysted metacercariae present in different organs such as gills, spleen, liver, kidney, and muscles. The collected encysted metacercariae were of the family Cyathocotylidae (Prohemistomum vivax) with a prevalence of 25%. Different cell-mediated immune responses such as Major histocompatibility class II alpha (MHC-IIα), Toll-like receptor 7 (TLR-7), Interleukin (IL-8), and Clusters of differentiation 4 (CD4) were assessed in different organs such as gills, spleen, liver, kidney, and muscles which revealed an elevation in different genes in infected organs as a reaction from the body against parasitic infection. In addition, the liver enzymes; aspartate aminotransferase (AST), and alanine aminotransferase (ALT), were assessed in the serum of O. niloticus as well as blood glucose, cortisol levels, and lysozyme activity were estimated to record higher levels in the infected fish in comparison with the control non-infected ones.