Gold nanoclusters offer useful photophysical properties and are extensively used as fluorescent labels in biomedical applications. Conventional drug administrative methods can face disadvantages such as poor solubility and low bioavailability of drugs. In order to overcome these limitations, the need of drug delivery vehicles arises. Here we report quantitative insights into the interaction of antibiotic drugs tetracycline, oxytetracycline, and rolitetracycline with protein (HSA) coated gold nanoclusters (PCGNCs) and that of (PCGNCs + drug) complex with deoxyribonucleic acid to explore drug transport abilities and potential in drug delivery. A combined calorimetric and spectroscopic approach has been employed to meet objectives. Exothermic heat of interaction suggest that polar association takes place between tetracycline or oxytetracycline and PCGNCs whereas rolitetracycline with pyrrolidinomethyl group shows endothermic heat of interaction. PCGNCs offer improved binding to drugs as compared to that with just the protein. These drug bound PCGNCs are further observed to undergo strong association with DNA in intercalation mode. Exothermic heats of interaction of (PCGNCs + tetracycline) and (PCGNCs + oxytetracycline) with DNA reveal that polar interactions play a significant role in binding whereas (PCGNCs + rolitetracycline) favors entropy driven process. Thermodynamic information associated with structural properties of the drugs and their carriers provide essential guidelines for developing effective drug delivery systems.