Oxytetracycline (OTC), an approved antibiotic for aquaculture, is under strict control and regulatory endeavour. This study compared the effects of oral administration of graded doses of OTC comprising the therapeutic (80 mg/kg biomass/day), subtherapeutic (40 mg) and overdoses (240, 400 and 800 mg) in male Nile tilapia Oreochromis niloticus fries (0.64 ± 0.02 g) when fed for 10 consecutive days and observed for 22 days post-OTC-dosing (POD) period. A dose-dependent reduction in food intake, survival and muscle calcium, chloride, malondialdehyde and superoxide dismutase was observed, while the muscle glucose significantly increased. However, the changes were reversible with dose cessation. The fries of the therapeutic dose group recorded the maximum biomass, while the overdosed groups recorded a significant decline in weight gain. On day 10 of dosing, all groups' muscle OTC residues peaked. The residues in the subtherapeutic and therapeutic dose groups were lowered below the maximum residue limit (MRL) of 100 ng/g on day 10 POD. The residues were further reduced close to the MRL in the overdosed groups on day 22 POD. The fries tolerated the therapeutic dose well and showed effective adaptive responses. Considering muscle residue accretion and physiological responses, OTC can be endorsed as a safe drug for in-feed administration to tilapia fries. However, the sensible use of this approved drug is essential for sustainable aquaculture.