Currently, the use of phytogenic additives and nanoparticles formulation in fish diets raises great worldwide interest. However, studies on the outcomes of their combination in farmed fish feeding are scarce. Hence, an experiment was planned to examine the effect of chitosan nanoparticle (ChNP), thymol (THY) or their mixture (THY + ChNP) supplementation on growth, whole-body composition, hematological profile, biochemical parameters, intestinal bacterial count, digestive enzymes, and intestinal histomorphology of Oreochromis niloticus. Fish (4.97 ± 0.02 g) were randomly distributed into 4 different treatments. The control group was fed a basal diet, while the other three groups were fed diets supplemented with THY (0.5 g/kg diet), ChNP (5 g/kg diet), and THY + ChNP at the same levels. Results showed that interaction synergistic effect was apparent between the supplemented THY and ChNP on the enhancement of feed and protein utilization, lymphocyte count, HCT, MCV, and MCHC values together with catalase, lipase, and protease activities. The individual THY or ChNP addition to the fish diet significantly improved growth performance indicators, feed utilization, erythrogram profile, oxidative stress parameters, lipase enzyme activity, and lipid sedimentation. Intestinal villus length was significantly increased in ChNP and THY + ChNP supplemented groups. A significant drop of the total anaerobic and aerobic intestinal bacterial count was apparent in THY and ChNP supplemented groups. Conclusively, although the individual addition THY or ChNP improved growth and some health indications, a notable synergistic interaction was obvious following their co-addition in most indicators.