This research developed a novel bioadhesive drug delivery system, poly(d,l-lactide-co-glycolide)/montmorillonite (PLGA/MMT) nanoparticles, for oral delivery of paclitaxel. Paclitaxel-loaded PLGA/MMT nanoparticles were prepared by the emulsion/solvent evaporation method. MMT was incorporated in the formulation as a matrix material component, which also plays the role of a co-emulsifier in the nanoparticle preparation process. Paclitaxel-loaded PLGA/MMT nanoparticles were found to be of spherical shape with a mean size of around 310nm and polydispersity of less than 0.150. Adding MMT component to the matrix material appears to have little influence on the particles size and the drug encapsulation efficiency. The drug release pattern was found biphasic with an initial burst followed by a slow, sustained release, which was not remarkably affected by the MMT component. Cellular uptake of the fluorescent coumarin 6-loaded PLGA/MMT nanoparticles showed that MMT enhanced the cellular uptake efficiency of the pure PLGA nanoparticles by 57–177% for Caco-2 cells and 11–55% for HT-29 cells, which was dependent on the amount of MMT and the particle concentration in incubation. Such a novel formulation is expected to possess extended residence time in the gastrointestinal (GI) tract, which promotes oral delivery of paclitaxel.