The nucleophosmin 1 (NPM1) mutation is one of the most frequent subtypes in acute myeloid leukemia (AML). Under the conditions of FLT3-internal tandem duplications (FLT3-ITD) and/or DNMT3A co-mutations or adverse cytogenetics, the originally favorable prognosis will deteriorate. In recent years, studies have found that multiple endocrine neoplasia protein (Menin) inhibitors targeting Menin-KMT2A complex can downregulate the overexpression of leukemia causing genes HOX (homeotic gene) and MEIS1 (myeloid ecotropic viral integration site 1) in NPM1-mutated AML, demonstrating remarkable anti-leukemia activity. This article aims to review the mechanism and clinical research of Menin inhibitors, novel small molecule targeted drugs in NPM1-mutated AML, as well as the resistance mechanism of Menin inhibitors, hoping to provide promising approaches for the subsequent treatment of NPM1-mutated AML patients.