Fish gut is a versatile organ serving as the primary pathway for invasion by pathogens, particularly parasites, playing a crucial role in modulating the intestinal adaptive immune response. This study aimed to investigate the cellular-mediated reaction, mucosal acidity, and the expression of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), and CD68 in the intestines of catfish, Clarias gariepinus, naturally infected with helminths. Forty catfish were collected from the Nile River and examined for intestinal parasites. The intestinal tissues of the control and infected fish were fixed for histochemical and immunohistochemical studies. Two groups of helminths were found: cestodes Tetracampos ciliotheca and Polyonchobothrium clarias, and nematodes Paracamallanus cyathopharynx, with a prevalence rate of 63.63%, 18.0%, and 18.0%, respectively. Our results showed that the infected fish had a statistically significant rise in the activity of immune cells, including mast cells, eosinophil granular cells, and dendritic cells. This correlated with upregulation in the expressions of PCNA, VEGF, and CD68. Histochemical analyses demonstrated a marked increase in acidic mucus production, Sudan black B, and bromophenol mercury blue. This study enriches our understanding of the evolution of vertebrate immunity in combating intestinal parasitic infections and the host’s adaptive responses.