Patients with acute myeloid leukemia (AML) who relapse after the first allogeneic hematopoietic stem cell transplantation (allo-HSCT) are confronted with an extremely poor prognosis, primarily due to the dearth of effective treatment strategies. In light of this critical clinical challenge, we embarked on an in-depth analysis of second salvage allo-HSCT in this high-risk patient population. Between 2019 and 2023, a total of 20 patients diagnosed with relapsed or refractory (r/r) AML received second salvage allo-HSCT at our center. Among these patients, 14 had a mean leukemic cell load of 44.2% (ranging from 5.5 to 97%) in the bone marrow, while the remaining 6 presented with extramedullary lesions. With a median follow-up period of 14.5 months (ranging from 1 to 36 months), 9 patients managed to survive in a leukemia-free state. The expected 2-year overall survival (OS) and leukemia-free survival (LFS) rates were both (45.5 ± 14.0)%. Among the 11 patients who succumbed to the disease, the causes of death were as follows: 1 case of implant failure, 2 cases of severe pneumonia, 1 case of pulmonary graft-versus-host disease (GVHD), and 7 cases of leukemia progression. Our research clearly demonstrates that second allo-HSCT serves as an effective salvage therapy for r/r AML patients following the first transplantation. Moreover, its safety profile is relatively manageable, suggesting its potential value in the clinical treatment of such patients.