This study aimed to develop an oral delivery system using clay-based organic–inorganic hybrid materials to improve the bioavailability of the drug, flurbiprofen, which is poorly soluble in water. 3-aminopropyl functionalized magnesium phyllosilicate (AMP clay) was synthesized by a one-pot direct sol-gel method, and then flurbiprofen (FB) was incorporated into AMP clay (FB-AMP) at different drug/clay ratios. The structural characteristics of AMP and FB-AMP formulation were confirmed by X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. Among tested formulations, FB-AMP
(3)
, dramatically increased the dissolution of FB and achieved rapid and complete drug release within 2 hours. More than 60% of FB was released from FB-AMP
(3)
after 30 minutes; the drug was completely dissolved in the water within 2 hours. Under the acidic condition (pH 1.2), FB-AMP
(3)
also increased the dissolution of FB by up to 47.1% within 1 hour, which was three-fold higher than that of untreated FB. Furthermore, following an oral administration of FB-AMP
(3)
to Sprague-Dawley rats, the peak plasma concentration and area under the plasma concentration-time curve of FB increased two-fold, and the time to reach the peak plasma concentration was shortened compared with that in the untreated FB. This result suggests that the oral drug delivery system using clay-based organic–inorganic hybrid material might be useful to improve the bioavailability of FB.