Gastric ulcer (GU), a common digestive system disorder in clinical practice, often arises from excessive alcohol consumption and other factors that irritate the gastric mucosa. Effective treatment of GU remains challenging due to the poor targeting, limited efficacy, and significant side effects associated with current therapeutic approaches. To address these limitations, we developed a microenvironment-responsive hydrogel composed of sodium alginate (SA) and chitosan (CS), incorporating MnO ₂ nanoparticles and pachymic acid (PA). This hydrogel was designed to evaluate its therapeutic potential for GU treatment in both in vitro and in vivo models. The SA/CS hydrogel system rapidly formed in response to acidic gastric conditions, leveraging the microenvironment to enhance therapeutic efficacy. Encapsulated MnO ₂ nanoparticles could scavenge reactive oxygen species (ROS), mitigating oxidative stress, while PA further alleviated oxidative damage. In vitro studies demonstrated that this hydrogel system significantly promoted the migration of gastric mucosal epithelial cells (GES-1) and reduced oxidative stress-induced damage under H ₂ O ₂ stimulation. Furthermore, in vivo evaluations using animal models of ethanol-induced acute GU and acetic acid-induced chronic GU confirmed the hydrogel’s pronounced anti-ulcer effects. These results underscore the potential of MnO ₂ -and PA-loaded SA/CS hydrogels as a safe, targeted, and effective therapeutic strategy for ethanol-induced gastric injury. This novel approach offers a promising foundation for the development of future gastric ulcer treatments.