Acetylsalicylic acid (ASA) is a clinical drug with multiple effects, including prevention of cardiovascular adverse events and anti-cancer effects. However, gastrointestinal side effects, such as gastrointestinal ulcers and bleeding, limit the use of ASA and reduce patient compliance. Various studies have investigated the mechanisms of ASA-induced gastrointestinal injury, and many medicines have been reported to be effective in preventing and treating the adverse gastrointestinal effects of ASA. New formulations of ASA have demonstrated milder gastrointestinal injury than ASA alone. In this article, we summarized the mechanisms of ASA-induced gastrointestinal injury, drugs that resist gastrointestinal side effects of ASA, and progress in research on formulation improvement of ASA to help resolve the clinical dilemma of ASA usage.