In this study, we highlight the potential of the mucoadhesive film made from a poly(ethylene oxide)/hydroxypropyl-β-cyclodextrin (PEO/CD) mixture in the oromucosal delivery of hydrophilic drugs, with a specific focus on dexamethasone phosphate disodium salt (Dexa). CD formed a complex with Dexa in solution and did not interact with mucin as highlighted from the spectrophotometric and spectrofluorimetric analysis. Similarly, CD and PEO did not affect mucin conformation, suggesting no direct interaction between the unstirred water layer and film components. Remarkably, PEO/CD/Dexa films dissolved more slowly than those made of PEO alone also in phosphate-buffered saline (PBS) pH 6.8 and gave a time-control on Dexa delivered dose. These combined effects resulted in a higher amount of Dexa accumulated in the mucosa, which can be highly beneficial in case of local diseases. Furthermore, Dexa amount able to diffuse through porcine buccal mucosa was lower when film contained CD, highlighting how CD can act as a modulator of drug transport also in the case of water-soluble drugs. In summary, our results demonstrate the versatility of PEO/CD films in mucosal delivery of hydrophilic corticosteroids paving the way to a novel approach in the treatment of mouth diseases.