Objective Aspirin usage is associated with increased risk of gastrointestinal bleeding. The present study explored the potential of teprenone, an antiulcerative, in preventing aspirin-related gastric mucosal injuries. Methods 280 patients with coronary diseases, naïve to aspirin medication, were admitted between 2011 and 2013 at the First Affiliated Hospital of Zhejiang Chinese Medical University and randomized into two groups (n = 140). The aspirin group received aspirin enteric-coated tablets 100 mg/day, while the aspirin+teprenone group received teprenone 50 mg 3 times/day along with aspirin. The patients were recorded for gastrointestinal symptoms and gastric mucosal injuries during a follow-up period of 12 months with 3-month intervals. Results During the 3-month follow-up, no significant difference was observed in the incidence rate of gastrointestinal symptoms between the two groups (P = 0.498). However, the incidence rate of gastrointestinal symptoms was significantly lower in the aspirin+teprenone group than in the aspirin group during the follow-ups at 6 months (P = 0.036) and 12 months (P = 0.036). The incidence rate of gastric mucosal injuries in the aspirin group was significantly increased at 12 months compared to that at 3 months (P = 0.016). The incidence rates at 12 months and cumulative for the entire follow-up period in the aspirin+teprenone group were both significantly lower than those of the aspirin group (P = 0.049 and P = 0.001, respectively). Conclusion Long-term use of low-dose aspirin causes varying degrees of gastric mucosal damages and gastrointestinal symptoms; the severity will increase within a certain range with the extension of medication duration. Teprenone mitigates the gastrointestinal symptoms caused by low-dose aspirin, lowering both the incidence and severity of gastric mucosal injuries and exerting a positive protective effect.