Electrospinning was used to prepare core/shell fibers containing the active pharmaceutical ingredients indomethacin (IMC) or mebeverine hydrochloride (MB-HCl). The shell of the fibers was fabricated from the pH sensitive Eudragit S100 polymer, while the drug-loaded core was based on the mucoadhesive polyethylene oxide (PEO). Three different drug loadings (from 9–23% w/w of the core mass) were prepared, and for MB-HCl two different molecular weights of PEO were explored. The resultant fibers generally comprise smooth cylinders, although in some cases defects such as surface particles or flattened or merged fibers were visible. Transmission electron microscopy showed all the systems to have clear core and shell compartments. The drugs are present in the amorphous physical form in the fibers. Dissolution tests found that the fibers can effectively prevent release in acidic conditions representative of the stomach, particularly for the acidic indomethacin. After transfer to a pH 7.4 medium, sustained release over between 6 and 22 h is observed. Given the mucoadhesive nature of the PEO core, after dissolution of the shell the fibers will be able to adhere to the walls of the intestinal tract and give sustained local drug release. This renders them promising for the treatment of conditions such as irritable bowel disease and colon cancer.