Gastrointestinal (GI) anastomosis is a usual procedure in the context of GI cancer surgeries. Performing an anastomosis may be complicated by infection, bleeding, anastomotic stricture, and anastomotic leakage. Anastomosis leakage is one of the devastating complications after performing an anastomosis which can be associated with several preoperative, intraoperative, and postoperative risk factors. Gender, body mass index, chemoradiotherapy, and underlying disease are preoperative risk factors for anastomosis leakage. In addition, surgical technique, operation time, tumor characteristics, blood loss, and blood transfusion are intraoperative risk factors. Diverting stoma and intestinal microbiota are assumed as post-operative risk factors for anastomosis leakage. In this comprehensive review, we aimed to describe risk factors of anastomosis leakage, especially blood transfusion. Blood transfusion can affect anastomotic healing by interfering with microcirculation, anastomotic healing phases, and the inflammatory phase of anastomosis healing. Compromised microcirculation caused by transfusion is one of the possible mechanisms for the failure of the anastomoses.