Abstract: Acute myeloid leukemia (AML) exhibits marked biological heterogeneity, and molecular subtyping is a key determinant of therapeutic response and prognosis. With advances in omics technologies and precision diagnostics, targeted therapies directed at defined genomic lesions have become an integral component of AML therapeutics. Although KMT2A rearrangements and NPM1 mutations arise from distinct origins, both converge to aberrantly activate the HOX/MEIS1 transcriptional program, thereby sustaining self-renewal of leukemia stem/progenitor cells and impeding differentiation, which in turn drives leukemogenesis and disease progression. Menin, a nuclear scaffold protein encoded by the tumor suppressor gene MEN1, assembles transcriptional complexes with KMT2A and its fusion proteins, recruits cofactors, and stabilizes the oncogenic HOX/MEIS1 network. These insights provide a clear biological rationale for therapeutic disruption of the menin–KMT2A interaction. In recent years, multiple menin inhibitors have entered clinical evaluation, with early data demonstrating clinical activity in AML subtypes harboring KMT2A rearrangements or NPM1 mutations. Against this backdrop, this review synthesizes advances in the research and clinical application of menin inhibitors in AML, integrating pharmacologic mechanisms, clinical evidence, and safety profiles. Resistance mechanisms—including acquired MEN1 hotspot mutations and epigenetic/transcriptional reprogramming—are also examined, and potential combination strategies and directions for next-generation agent development are discussed to inform subsequent clinical practice.