Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by immune system dysfunction. Despite the availability of various anti-inflammatory drugs, they exhibit low therapeutic efficacy with systemic side effects. In this study, we developed oral anti-inflammatory polyamine-based nanomedicines for the treatment of ulcerative colitis. Polyamine-bearing nanoparticles were prepared by the self-assembly of hyaluronic acid in organic solvents and crosslinking with branched oligoethyleneimine. Polyamine nanoparticles were found to suppress excessive inflammatory responses by scavenging the reactive oxygen species (ROS). Moreover, these nanoparticles inhibited enzymatic degradation and targeting of inflamed intestinal tissues. Additionally, they suppressed the inflammatory responses and recovered the pathological disorders in the colon of an ulcerative colitis mouse model. Therefore, polyamine-based nanomedicines exhibit great potential as biocompatible ROS-scavenging drugs for the treatment of IBD.