Vancomycin is a potent antibacterial drug that suffers from poor bioavailability due to its poor water solubility and relatively high molecular weight. Consequently, the application of vancomycin to treat bacteria-induced disease is limited. In this study, the ability of a temperature-stimulated propargyl acrylate-poloxamer nanocomposite (PAPN) system to encapsulate and release vancomycin is investigated. A controllable encapsulation and release system can be used to not only increase and prolong the bioavailability of vancomycin but also activate vancomycin with a temperature change. The PAPN system was prepared using an emulsion polymerization of propargyl acrylate followed by a surface decoration with a poloxamer at a precisely controlled grafting density. The activity of the PAPN system loaded with vancomycin is compared to that of the free drug and unmodified propargyl acrylate nanoparticles. It is shown that the activity of the PAPN system loaded with vancomycin is comparable to that of a freshly prepared, free-floating vancomycin solution. Upon storage, the activity of the free vancomycin in solution decreases, while the PAPN system loaded with vancomycin retains its high activity. Additionally, the PAPN system is able to effectively encapsulate and deactivate vancomycin until heated above a lower critical solution temperature (LCST). At temperatures above the LCST, the PAPN system releases vancomycin restoring the activity of the drug.