Herbal supplements are suitable for improving fish growth, health, and tolerance to environmental perturbations. In this study, the effects of bitter leaf Vernonia amygdalina extract (BLE) on growth, hematology, liver health, resistance to Aeromonas hydrophila, and heat stress response in Nile Tilapia Oreochromis niloticus were investigated. Experimental fish (average weight = 31 ± 0.30 g [mean ± SD]) held in concrete tanks were fed a control (CT) diet or a diet supplemented with 1, 3, or 5% BLE for 8 weeks. After 4 and 8 weeks, Nile Tilapia that received diets enriched with BLE showed significantly improved weight gain and feed conversion ratio compared to fish that were given the CT diet. Fish that were fed 1% BLE performed significantly better than fish fed the other BLE diets with respect to growth. Fish that were given experimental diets, particularly the 1% BLE diet, showed increased levels of white blood cells (WBCs), red blood cells (RBCs), hemoglobin (HGB), hematocrit (HCT), and total protein compared to fish fed the CT diet. After a challenge test with A. hydrophila, BLE‐fed fish showed significantly lower cumulative mortality (%) in comparison with the CT group. Dietary BLE supplementation did not adversely affect the liver of fish, as aspartate aminotransferase and alanine transaminase levels were lower than those in CT fish. Nile Tilapia that received BLE diets showed significantly enhanced WBCs, RBCs, HGB, and HCT after exposure to heat stress relative to the CT group. Among the BLE levels used in this study, the 1% BLE diet consistently produced significant responses on most variables investigated when compared to the higher BLE dietary supplements. Nile Tilapia production can be improved with BLE supplementation in diets, especially at a rate of 1%.