A variety of oral administrative systems such as enterically coated tablets, capsules, particles, and liposomes have been developed to improve oral bioavailability of drugs. However, they suffer from poor intestinal localization and therapeutic efficacy due to the various physiological conditions and high shear fluid flow. Fabrication of novel microdevices combined with the introduction of controlled release, improved adhesion, selective targeting, and tissue permeation may overcome these issues and potentially diminish the toxicity and high frequency of conventional oral administration. Herein, thin, asymmetric, poly(methyl methacrylate); PMMA microdevices were fabricated with multiple reservoirs using photolithography and reactive ion etching. They were loaded with different individual model drug in each reservoir. Enhanced bioadhesion of the microdevices was observed in the presence of a conjugated of targeting protein; tomato lectin to the PMMA surface. As compared to drug encompassing hydrogels, an increase in drug permeation across the caco-2 monolayer was noticed in the presence of a microdevice loaded with the same drug-hydrogel system. Also, the release of multiple drugs from their respective reservoirs was found to be independent from each other. The use of different hydrogel systems in each reservoir showed differences in the controlled release of the respective drugs over the same period of release. These results suggest that in the future, the microfabricated unidirectional multi-drug releasing devices will have an impact over the oral administration of a broad range of therapeutics.