Gastrointestinal bleeding (GIB) is a potentially fatal and avoidable medical condition that poses a burden on global health care costs. The rate of major GIB related to the use of some direct acting oral anticoagulant drugs (DOACs), is higher than that detected in warfarin users. Current strategies in the treatment of GIBs in patients receiving warfarin or DOACs (vitamin K, activated charcoal; hemodialysis; recombinant factor VIIa; [activated] prothrombin complex concentrates) including indications for the treatment of bleeding based on different degrees of severity of the episodes, is reported in this article. Potential preventive strategies to mitigate the risk of GIBs (e.g. upper endoscopy/biopsy, colon cancer screening; eradication of Helicobacter pylori prior to starting anticoagulation; use of proton-pump inhibitors, identification of risk factors for bleeding) are also reported as well as the fact that some of them have not been tested so far in patients receiving DOACs. Antidotes that experimentally reverse the anti-coagulant effect of dabigatran (Idarucizumab; BI 655075; Boehringer Ingelheim); of rivaroxaban, apixaban, or edoxaban (Andexanet alfa, r-Antidote, PRT064445; Portola Pharmaceuticals) or of all DOACs (Aripazine, PER-977, ciraparantag; Perosphere Inc.) are discussed. Likewise, population pharmacokinetics modeling related to the rate of major DOACs-related GIBs is presented. It is also emphasized that the occurrence of GIB reflects the presence of patients at the highest risk for adverse outcomes. Finally, the implications of the concept that patient characteristics and the severity of illness (i.e. comorbidities) exert a greater impact on the risk of GIB than the type of antithrombotic agent employed, are analyzed.