Esophageal mucosal resection for superficial esophageal cancer can lead to postoperative esophageal stricture, with current preventive measures being insufficient. Sprayable wound dressings containing hydrophobized microparticles exhibit strong adhesion. This study aimed to investigate the preventive effects of hydrophobized microparticles on esophageal stenosis following endoscopic submucosal dissection. Circumferential esophageal endoscopic submucosal dissection was performed on miniature swine (n = 6). Swine were categorized into two groups: those sprayed with hydrophobized microparticles (sprayed group) and those not sprayed (non-sprayed group). Hydrophobized microparticles were sprayed onto the sprayed group on Days 0, 3, and 7 of endoscopic submucosal dissection. The non-sprayed group underwent endoscopy on the same days. Esophageal stricture rate, submucosal inflammatory cell infiltration, submucosal fibrosis, and thickening of the muscular layer were compared between the groups on Day 14 of endoscopic submucosal dissection. Spraying of hydrophobized microparticles was easily performed using an existing endoscopic spraying device. The esophageal stricture rate was significantly lower in the sprayed group than in the non-sprayed group (76.1% versus 90.6%, p < 0.05). The sprayed group showed suppression of inflammatory cell infiltration in the submucosal layer (p < 0.01) and thickening of the muscular layer (p < 0.01). Sprayable tissue-adhesive hydrophobized microparticles reduce the stricture rate after esophageal ESD by inhibiting inflammatory cell infiltration, submucosal fibrosis, and thickening of the muscular layer. The use of hydrophobized microparticles for preventing post-endoscopic submucosal dissection esophageal stenosis offers a promising avenue for clinical applications in endoscopic procedures, potentially improving patient outcomes.