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 are fabricated with multiple reservoirs using photolithography and reactive ion etching. They are loaded with different individual model drug in each reservoir. Enhanced bioadhesion of the microdevices is 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 is noticed in the presence of a microdevice loaded with the same drug–hydrogel system. Also, the release of multiple drugs from their respective reservoirs is found to be independent from each other. The use of different hydrogel systems in each reservoir shows differences in the controlled release of the respective drugs over the same release period. These results suggest that, in the future, microfabricated unidirectional multi-drug releasing devices will have an impact on the oral administration of a broad range of therapeutics.