The main objective of controlled drug delivery is to deliver a specific amount of drug over a predetermined period of time in a controllable manner and improve the drug therapy effectiveness. Interpenetrating network (IPN) and core-shell nanofibers fabricated from polyvinyl pyrrolidone (PVP) and polyvinyl acetate (PVAc) are used in this work to control the release behavior of tetracycline hydrochloride (TCH) antibiotic. Hydrophilic PVP polymer releases drugs immediately due to its solubility in the medium. Hydrophobic PVAc polymer provides structural integrity of the nanofiber scaffold in the case of IPN morphology and adds a barrier to drug diffusion in the core-shell organization with PVAc as the shell. In this study, the release and antimicrobial behavior against Pseudomonas aeruginosa in simulated wound fluids and tryptic soy broth media is investigated. The images from SEM and TEM establish that encapsulation of TCH in the polymers alters the average diameter of the nanofibers. Cumulative release of the drug from IPN nanofibers is proportional to the amount of drug loaded. However, the percentage of the drug released reduces with an increase of drug loading in the nanofibers. Core-shell nanofibers exhibit slow release of TCH over a long period of time and the released amount is proportional to the amount of drug loaded in the core polymer.