Despite the success of minimally-invasive endoscopic submucosal dissection (ESD) for the treatment of early gastrointestinal cancer, additional symptoms after ESD, including contracture, perforation, bleeding, and esophageal stricture remain. Conventional wound dressings were ineffective in preventing stricture because of poor stability of underwater-adhesives on living tissues. Here, we present a microparticle-based wound dressing with underwater adhesive stability for the treatment of gastrointestinal tract wound healing after ESD. Monodisperse microparticles composed of hydrophobically-modified Alaska pollock gelatin were prepared by self-assembly of gelatin in water-ethanol mixed solvents and thermal crosslinking. Hydrophobic modification of gelatin with aliphatic aldehydes increased adhesion strength to gastric and esophageal submucosal tissues through hydrophobic interaction with living tissues and cohesion force. Optimal hydrophobic modification drastically improved underwater stability of microparticles compared to that of non-modified gelatin and formed a thick, integrated hydrogel layer on tissues. Histological observation of rat skin wound healing models showed that hydrophobically-modified gelatin microparticles decreased the expression levels of α-smooth muscle actin in the dermis layer and could suppress fibrosis and inflammation after ESD. The microparticle wound dressing with high underwater-adhesive stability has enormous therapeutic potential to promote wound healing in the gastrointestinal tract and prevent additional symptoms after ESD. STATEMENT OF SIGNIFICANCE: The goal of this study was to develop wound dressing with strong tissue-adhesive property to living tissues for promoting wound healing after ESD treatment. Monodisperse microparticles composed of hydrophobically-modified Alaska pollock gelatin were prepared by self-assembly of gelatin in water-ethanol mixed solvents and thermal crosslinking. Hydrophobic modification of gelatin with aliphatic aldehydes enhanced adhesion strength to gastric and esophageal submucosal tissues through hydrophobic interaction with living tissues and cohesion force. Optimal hydrophobic modification drastically improved underwater stability of microparticles. The in vivo studies were performed to evaluate the ability of this colloidal wound dressing to suppress fibrosis. This new biomaterial has enormous potential to promote wound healing after ESD.