Oral inflammatory diseases are highly prevalent in the worldwide population. Topical treatment of inflammation is challenging due to dilution effects of saliva and crevicular fluid. Thus, there is a great medical need to develop smart anti-inflammatory drug delivery systems for mucosa treatment. We compared two promising anti-inflammatory dendritic poly(glycerol-caprolactone) sulfate (dPGS-PCL) polymers for their applicability to the oral mucosa. Using an ex vivo porcine tissue model, cell monolayers, and full-thickness 3D oral mucosal organoids, the polymers were evaluated for muco-adhesion, penetration, and anti-inflammatory properties. The biodegradable dPGS-PCL97 polymers adhered to and penetrated the masticatory mucosa within seconds. No effects on metabolic activity and cell proliferation were found. dPGS-PCL97 revealed a significant downregulation of pro-inflammatory cytokines with a clear preference for IL-8 in cell monolayers and mucosal organoids. Thus, dPGS-PCL97 exhibits excellent properties for topical anti-inflammatory therapy, suggesting new therapeutic avenues in the treatment of oral inflammatory diseases.