Abstract This study evaluated the dietary lysozyme (DSLY) effect on the growth performance, health status, and disease resistance in hybrid red tilapia (Oreochromis niloticus x O. mossambicus). Fish were fed dietary DSLY at 0, 1, 2, and 3 g/kg diet (L0-L3, respectively) for 60 days, followed by a challenge with Streptococcus agalactiae. Fish-fed diets (DSLY) showed significant improvements in growth, carcass composition, digestive enzyme activity, and intestinal histomorphometry compared to control groups, specifically in the L2 and L3 groups. Fish fed with DSLY had lower gut bacterial counts than the control. Fish-fed DSLY positively affected hemato-biochemical indices compared to the control group, especially in the 2 and 3 g/kg diets. Comparing fish fed DSLY to those fed 0 g/kg lysozyme, particularly in the 2 and 3 g/kg diets, revealed a significant decrease in MDA levels along with an increase in antioxidant (SOD and CAT) and immunological indices. Fish-fed DSLY, after the challenge with S. agalactiae showed a lower mortality rate than the control. The histological structure of the intestines and stomach of fish that fed DSLY improved. These results suggest that fish-fed DSLY enhanced their intestinal health and growth, boosted their immune responses, and raised their resistance to S. agalactiae.