Periodontitis is a chronic inflammatory disease characterized by a dysregulated interaction between the subgingival microbiota and the host immune response, leading to the accumulation of excessive inflammatory mediators and progressive tissue destruction. In this study, we first established a correlation between polyamine accumulation and periodontal inflammation by testing clinical samples of gingival crevicular fluid. To test the hypothesis that polyamine scavenging will benefit periodontitis treatment, we developed a polyamine-capturing hydrogel loaded with charge modified dodecyl sulfobutyl ether-β-cyclodextrin (SCDC12). The self-assembled SCDC12 nanoparticles effectively alleviated the cellular oxidative stress, improved cell viability, and inhibited the expression of proinflammatory factors by capturing polyamines in vitro. In addition, SCDC12 inhibited the growth of periodontal pathogens and biofilm formation. In a rat periodontitis model, SCDC12 hydrogel inhibited the expression of the rate-limiting enzyme in polyamine anabolism, downregulated the level of proinflammatory factors, and reduced local inflammatory response and alveolar bone loss. Our findings highlight SCDC12 as a promising polyamine scavenger, offering a novel therapeutic strategy for periodontitis treatment by restoring polyamine homeostasis.