Transmucosal drug administration represents a potential strategy for enhancing treatment efficacy and reducing side effects by avoiding the first-pass effect into the systemic circulation and delivering therapeutics directly to the target disease site. However, many challenges still remain in its clinical application, including low drug availability and limited retention time in the mucosa. The burgeoning advancement of nanotechnologies offers great potential to overcome the above limitations, leveraging their distinct advantages of high drug-loading capacity and strong permeability. In this review, the latest developments of nanoparticles (NPs) in transmucosal drug delivery as well as their clinical applications are discussed.