Hydrogen sulphide (H2S) serves as a vital gastric mucosal defence under acid condition. Non‐steroidal anti‐inflammatory drugs (NSAIDs) are among widely prescribed medications with effects of antipyresis, analgesia and anti‐inflammation. However, their inappropriate use causes gastric lesions and endogenous H2S deficiency. In this work, we reported the roles of a novel pH‐controlled H2S donor (JK‐1) in NSAID‐related gastric lesions. We found that JK‐1 could release H2S under mild acidic pH and increase solution pH value. Intragastrical administration of aspirin (ASP), one of NSAIDs, to mice elicited significant gastric lesions, evidenced by mucosal festering and bleeding. It also led to infiltration of inflammatory cells and resultant releases of IL‐6 and TNF‐α, as well as oxidative injury including myeloperoxidase (MPO) induction and GSH depletion. In addition, the ASP administration statistically inhibited H2S generation in gastric mucosa, while up‐regulated cyclooxygenase (COX)‐2 and cystathionine gamma lyase (CSE) expression. Importantly, these adverse effects of ASP were prevented by the intragastrical pre‐administration of JK‐1. However, JK‐1 alone did not markedly alter the property of mouse stomachs. Furthermore, in vitro cellular experiments showed the exposure of gastric mucosal epithelial (GES‐1) cells to HClO, imitating MPO‐driven oxidative injury, decreased cell viability, increased apoptotic rate and damaged mitochondrial membrane potential, which were reversed by pre‐treatment with JK‐1. In conclusion, JK‐1 was proved to be an acid‐sensitive H2S donor and could attenuate ASP‐related gastric lesions through reconstruction of endogenous gastric defence. This work indicates the possible treatment of adverse effects of NSAIDs with pH‐controlled H2S donors in the future.