Oxytetracycline (OTC) is a widely used antibiotic in both freshwater and marine intensive aquaculture practices. Responsible use of antibiotics requires data on in vitro efficacy against pathogens of targeted species, as well as on biosafety and tissue residue level in each targeted host. Accordingly, experiments were designed to evaluate the biosafety and tissue residue level of OTC in a marine aquaculture candidate species, viz., snubnose pompano (Trachinotus blochii). Biosafety of OTC was assessed by administration of medicated feed both at the therapeutic dose (80 mg/ kg biomass) and 3, 5, and 10 times the therapeutic dose. Exposure was done both for the recommended duration of time (10 days) as well as two and three times higher than the recommended duration. Histological examination revealed moderate to severe tissue morphological changes in the liver, kidney, and gills of fish exposed to OTC. The liver was the first and most severely affected organ. Pathological effects in all the three selected organs were directly related to the dose and duration of OTC exposure. Further, tissue residue concentrations in the muscle of the group exposed to OTC at the therapeutic dosage for a duration of 10, 20, and 30-days were well below the maximum residual level prescribed by the European Commission and the US Food and Drug Administration, on day zero post-withdrawal, leaving its implications on consumer safety. Additionally, in vitro efficacy evaluation against marine fish pathogens of the target species, viz., Vibrio harveyi, Vibrio vulnificus, and Vibrio parahaemolyticus, showed that minimum inhibitory concentration and minimum bactericidal concentration ranged from 0.6 to 1.5 μg mL−1 and 2.5 to >320 μg mL−1, respectively. Altogether, the results will assist in the design and implementation of responsible use of OTC in aquaculture practices of T. blochii.