Oral administration is perhaps the most commonly used and acceptable route for drug delivery to patients, mainly due to its non-invasiveness, simplicity, and versatility. Conventional delivery media such as tablets or capsule-based formulations, however, could result in low drug bioavailability and insufficient therapeutic efficiency, especially for delivering biologics (e.g., peptide, protein, antibody, nucleic acid). Therefore, with the advancement of material science and micro-/nano-fabrication techniques, various carriers have been developed to protect drugs and improve their absorption in the gastrointestinal (GI) tract. Herein, we first summarized various types of drug molecules being used for oral administration. Then we discussed the major physiological barriers (including various biochemical, mucosal diffusion, and cellular permeation barriers) that hinder drug transportation and absorption, as well as the main targeting regions in the GI tract. On this basis, we reviewed recently emerged oral drug delivery platforms and discussed their widely investigated biomedical applications. Finally, we present future perspectives for materials science-enabled oral drug delivery platforms, and potential challenges for clinical translation.