BACKGROUND: Hemophilia, an uncommon yet consequential hereditary bleeding disorder, manifests as two clinically indistinguishable forms that hinder the normal functioning of the coagulation cascade. This impairment renders individuals more susceptible to excessive bleeding during significant surgical interventions. Moreover, individuals with severe hemophilia frequently encounter recurring hemarthrosis, resulting in progressive joint destruction and, subsequently, the need for hip and knee replacement surgeries. CASE SUMMARY: The patient was a 53-year-old man with hemophilia A as the underlying disease and had self-injected factor VIII twice weekly for several decades. He had undergone ankle fusion surgery for recurrent hemarthrosis at the Department of Orthopedic Surgery 1 mo prior and was referred to our department because of skin necrosis after a hematoma at the surgical site. An anterolateral thigh perforator free flap was created after three cycles of factor VIII administration in addition to the concomitant administration of tranexamic acid (TXA) (Transamin 250 mg cap, 1 cap tid, q8h). After the operation, from postoperative days (PODs) 1-5, the factor VIII dose and interval were maintained, and q12h administration was tapered to q24h administration after POD 6. Because the patient's flap was stable 12 d after the operation, factor VIII administration was tapered to twice a week. At 6 mo follow-up, the patient recovered well without any complications. CONCLUSION: To the best of our knowledge, there are very few reports of successful free flaps in patients with hemophilia, and none have been reported in patients with hemophilia A. Moreover, there are several reports on the efficacy of TXA in free flaps in general patients; however, there are no case reports of combining factor VIII and TXA in patients with hemophilia. Therefore, we report this case to contribute to future academic research.