The aim of this study was to determine the effects of Tribulus terrestris extract (TT) on growth performance, disease resistance and histopathological changes in intestine and liver tissues of Oreochromis mossambicus (Peters, 1852) first-feeding fry before and after exposure to Streptococcus iniae. Five isonitrogenous and isocaloric diets were formulated to contain 0 (control), 200, 400, 600, and 800 mg kg−1 TT. After feeding for 45 days, fish were infected with S. iniae and mortalities recorded. Final weight, weight gain and SGR of tilapia fry fed the 400 mg kg−1 TT diet were significantly greater than that of control diet. In the challenge experiment, the best survival rate was obtained with 400 mg kg−1 TT supplementation. Infection by S. iniae appeared to have a negative effect on histopathological findings and outcome than did TT-800 used alone. However, administration of TT (200 or 400 mg extract kg−1) resulted in overall improvement in the intestine and liver histopathology, emphasizing the protective potential of TT. The present study suggests the protective potential of TT in alleviating intestinal and hepatic damage that can occur after a S. iniae infection. It was concluded that 400 mg kg−1 TT can enhance growth and disease resistance during first–feeding of O. mossambicus fry. This suggests that TT may be an alternative to antibiotics in controlling streptococcal disease in tilapia culture.