Local administration of chemotherapeutic drugs to a tumor site in the oral cavity can provide high drug concentrations in the tumor area and reduce systemic side effects. In this work, catechol (Cat)-modified chitosan/hyaluronic acid (HA) nanoparticles (NPs), hereinafter referred to as Cat-NPs, were developed as a new carrier to deliver doxorubicin (DOX) to oral cancer cells. The Cat moiety of the NPs allowed the excellent adhesion of the carrier to the oral mucosa and sustained local delivery of DOX into the oral cavity. Cat-NPs were generated from Cat-functionalized succinyl chitosan and Cat-bearing HA via ionic gelation. Negatively charged and spherical Cat-NPs measuring approximately 160 nm in size were obtained. The modified NPs demonstrated superior mucoadhesive capability on ex vivo porcine oral mucosal tissues compared with the unmodified NPs. DOX could be loaded onto the modified NPs with a high loading capacity of 250 μg/mg, and sustained-release characteristics were observed. The DOX-loaded Cat-NPs (DOX-NPs) inhibited the growth of the HN22 oral squamous cell carcinoma cell line with a low IC. Moreover, the DOX-NPs were taken up, accumulated, and induced apoptosis in cells more extensively compared with free DOX. These findings reflect the potential use of the synthesized Cat-NPs as a new carrier for the local delivery of DOX to oral cancer cells. Further in vivo studies should be carried out to confirm the clinical applications of these NPs.Copyright © 2020 Elsevier B.V. All rights reserved.