Background: Acute myeloid leukemia (AML) harboring mixed lineage leukemia (MLL) rearrangement typically presents with high malignancy, poor remission rates, susceptibility to relapse, and a dismal prognosis. For these patients, achieving rapid remission followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important strategy, underscoring the importance of choosing the initial induction regimen. Mitoxantrone liposome (L-MIT) is a modified drug formulation that enhances antitumor activity and reduces toxicity. At present, there is no report on the efficacy and safety of the MEA regimen consisting of L-MIT combined with etoposide and cytarabine in patients with AML with MLL rearrangement. Case Description: We described four patients with MLL-rearranged AML who received L-MIT combined with etoposide and cytarabine (MEA) as induction therapy, evaluating efficacy and safety after one treatment cycle. Three patients achieved complete remission (CR), including two who reached minimal residual disease (MRD) negativity, and another patient achieved partial remission (PR). Currently, three patients received allo-HSCT, while one was in consolidation chemotherapy due to advanced age and financial limitations. The main adverse event was manageable myelosuppression, with one case remaining febrile without signs of infection, while the other three experienced varying degrees of infections. Gastrointestinal side effects were mild, with no liver or kidney damage, obvious cardiac toxicity, infusion reactions, or skin discoloration. Conclusions: The L-MIT-based MEA regimen showed promising efficacy with a favorable safety profile in patients with MLL-rearranged AML, suggesting that the MEA regimen could be one of the preferred therapeutic options for this population.