Objective To explore if antiplatelet or anticoagulant therapy increases the risk of transfusion requirement or postoperative hematoma formation in patients undergoing microvascular reconstruction for head and neck defects. Study Design Retrospective cohort study. Setting Departments of Otolaryngology–Head and Neck Surgery at the University of Alabama at Birmingham, the University of Colorado, and the University of California Irvine. Methods A multi‐institutional, retrospective review on microvascular reconstruction of the head and neck between August 2013 to July 2021. Perioperative antithrombotic data were collected to examine predictors of postoperative transfusion and hematoma. Results A total of 843 free flaps were performed. Preoperative hemoglobin, hematocrit, operative time, and flap type were positive predictors of postoperative transfusion in both bivariate (P < .0001) and multivariate analyses (P < .0001). However, neither anticoagulation nor antiplatelet therapy were predictive of postoperative transfusion rates and hematoma formation. Conclusion Antithrombotic regimens do not increase the risk of postoperative transfusion or hematoma in head and neck microvascular reconstruction. Based on this limited data, perioperative antithrombotic regimens can be considered in patients who may otherwise be at risk for these postoperative complications.