Although fish meal is considered the main animal protein source in fish diets, its high cost and unavailability limit its use in aquafeed. Recently, the search for other high-quality replacers of fish meal in aquatic feeds is being carried out with increased attentiveness. However, very few investigations have been performed to assess the possible use of whey protein concentrates (WPC) in Nile tilapia feeds. Five replacement percentages of fish meal with WPC (0%, 13.8%, 27.7%, 41.6%, and 55.5%) were assessed. WPC could replace the fish meal in Nile tilapia diets up to 27.7%, with improving the gut health, the total weight of survival fish, and immune status of fish challenged with Aeromonas hydrophila. High inclusion levels of WPC are not recommended in fish diets, since they negatively affected the intestinal and liver tissues and increased the level of cellular apoptosis, as indicated by the increased caspase 3 activity