Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract characterized by excessive reactive oxygen species (ROS) production and compromised epithelial barrier function. Reconstructing an intestinal mucus barrier with ROS-scavenging capability represents a promising therapeutic strategy for the prevention and treatment of IBD. In this study, a hyaluronic acid (HA)-based hydrogel designed to mimic the native mucus barrier was developed through modulation of the pKa of sulfhydryl groups, enabling controlled disulfide crosslinking and ROS-responsive degradation under physiological conditions. The resulting hydrogels exhibited tunable viscoelastic properties, degradability, and tissue adhesiveness, closely resembling the physical and functional characteristics of natural intestinal mucus. In vitroevaluations demonstrated excellent cytocompatibility, hemocompatibility, and resistance to bacterial penetration. The optimized ROS-scavenging HA hydrogel effectively protected intestinal epithelial cells against oxidative stress-induced damage and enhanced epithelial barrier integrity by upregulating tight junction proteins, including ZO-1 and occludin. In vivo studies showed significant suppression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), increased levels of anti-inflammatory mediators (IL-4 and IL-10), and restoration of mucosal architecture. Furthermore, the HA hydrogel promoted M2 macrophage polarization and modulated gut microbiota composition, thereby facilitating inflammation resolution and mucosal healing.