A variety of drugs are administered orally to control parasitic diseases in aquaculture. This study assessed the effects of oral dose and dosage of an antiparasitic agent emamectin benzoate (EB) on the safety and kidney, liver, and intestine tissue histoarchitecture of Oreochromis niloticus. The EB-medication for 21 days at the recommended dose caused about 2% mortalities, 25% reduced feed intake, and 6.52% biomass reduction. The results revealed a dose-dependent hepatotoxic, nephrotoxic, and intestinal toxic potential of EB and the relationship between medication and the functioning of vital organs. Degeneration of the renal tubules and tubular epithelium, glomerulopathy, vacuolation, inflammation and necrotized renal interstitium were observed in the kidney. The liver tissues had glycogen-type vacuolation, cytoplasmic degeneration, and vacuolation. The intestine exhibited loss of absorptive vacuoles, mucinous degeneration, necrotized intestinal villi, inflammation, and necrotized absorptive region. Lamina propria swelling was noticed in the intestine of the higher dosed groups. With the termination of medication, the specific pathological changes were reduced significantly, indicating the ability of fish to mount adaptive responses to recoup. Though the EB at the recommended dose caused mortalities, reduced feed intake, and biomass during the extended EB-dosing as well as at the higher doses, it is unlikely to produce adverse and irrevocable effects on O. niloticus at the dose of 50 μg/kg biomass/day for 7 consecutive days. The inclusion of EB in the aquaculture medicine list for managing the external parasites would help boost the tropical freshwater fish health and production.