Emamectin benzoate (EB) premix top-coated onto feed is extensively used to treat ectoparasitic crustacean infestations in aquaculture. This study evaluated the safety of EB-dosing in Nile tilapia Oreochromis niloticus at the recommended dose and dosage of 50 μg/kg biomass/day for 7 consecutive days (1X) and compared with control and 10 times the recommended dose (10X). Depletion of EB-residues in the edible muscle of 1X-dosed Nile tilapia was also studied. Mortality, behavioural changes, feed consumption, biomass, EB-residue depletion, and histopathological alterations in the kidney, liver and intestine were determined at slated intervals. Significant dose-dependent reduction in feed intake and biomass and insignificant mortalities were noted in 1X and 10X EB-dosed fish. In 1X EB-dosed fish muscle, the residues peaked on day 7 EB-dosing (9.72 ng/g) and decreased subsequently. Nevertheless, the residue levels were within the acceptable limit of the European Commission and the Canadian Food Inspection Agency even during the EB-dosing period. Histologically, tubule degeneration in the kidney, mild glycogen vacuolation in the liver, and loss of absorptive vacuoles, inflammation and disintegration of the epithelial layer in the intestine of Nile tilapia fed the 1X EB-diet were observed. The fish reverted back to their normal functions with time upon termination of oral-EB-dosing. This work contributed scientific data on the safety of EB particularly on the feed intake, growth reduction, mortality, histopathological alterations, and EB-residue levels in the edible tissues of Nile tilapia fed at the recommended dose and dosage, which suggested that EB-therapy might be reasonably risky in a tropical climate.