INTRODUCTION: Antibody-based immunotherapies are a class of therapeutics under active investigation in clinical trials for the treatment of acute myeloid leukemia (AML). Our review provides a comprehensive examination of trials published to date, focusing on recurrent challenges and promising aspects of antibody-based therapeutics. AREAS COVERED: We described antibody-based immunotherapies for AML, specifically, an overview of the most prominent antigen targets in published clinical trials investigating monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor therapies. Manuscripts and abstracts describing clinical trials investigating antibody-based therapies for AML published through December 2024, identified by searching Google Scholar and PubMed, were included. EXPERT OPINION: Antibody-based immunotherapies for AML have encountered limitations, including imperfect target antigens with significant associated toxicity such as myelosuppression, in addition to challenges specific to the AML patient population. The majority of trials have targeted CD33, CD123, CD371 (CLL1/Clec12), and CD47. For successful implementation of antibody-based therapeutics in AML treatment, future directions require creative applications of antibody-based therapeutics specifically engineered to minimize limiting toxicities and tailoring of therapies for this unique patient population.