Slow healing of gastric mucosa defects caused by endoscopic surgery is a common but severe clinical problem for lack of an effective treatment. Small intestinal submucosa (SIS) is a bio-derived extracellular matrix scaffold with remarkable repairing ability for soft tissue, but its rapid degradation and poor mechanical properties in the stomach environment limit its application for gastric mucosa regeneration. Herein, we modified SIS by genipin, a natural crosslinking agent, to improve its resistance against degradation in gastric juice and to promote the healing of gastric mucosa defects. The crosslinking characteristics of genipin-crosslinked SIS (GP-CR SIS) were evaluated by crosslinking degree, swelling ratio and FITR, respectively. GP-CR SIS was highly resistant to gastric juice digestion and had a great improvement in mechanical properties. Additionally, GP-CR SIS maintained excellent biocompatibility according to a cytotoxicity test, hemolysis test, and rat subcutaneous implant assay. In an in vivo study, we treated defected gastric mucosa with GP-CR SIS in a rabbit endoscopic submucosal dissection (ESD)-related ulcer model. After two weeks of surgical treatment, GP-CR SIS significantly expedited wound closure and ameliorated newly constructed tissue by providing a protective microenvironment for rapid granulation tissue formation and accelerating angiogenesis/re-epithelialization. In conclusion, this study demonstrates the huge therapeutic potential of GP-CR SIS scaffolds for accelerating defected gastric mucosa regeneration.