Nucleophosmin 1 (NPM1) mutation is a core molecular marker in adult acute myeloid leukemia (AML) and an ideal target for assessing subclinical disease burden (i.e., minimal residual disease [MRD]). This mutation has a significant clinical value in disease classification, treatment selection, and prognosis evaluation. In this review, we integrate the latest research advances and discuss the clinical applicability of targeted therapies, chemotherapy combined with anti-CD33 monoclonal antibodies, and allogeneic hematopoietic stem cell transplantation (allo-hematopoietic stem-cell transplantation). This review highlights the importance of dynamic MRD monitoring to optimize long-term disease management. We particularly focus on the mechanisms of drug resistance in NPM1-mutated AML (e.g., B-cell lymphoma 2 [BCL-2]/myeloid cell leukemia 1 [MCL-1] imbalance and metabolic adaptations) and characteristics of the Chinese population (mutation frequency, co-mutation profiles, and treatment response). This review aims to provide clinicians with a stratified diagnosis and treatment framework for NPM1-mutated AML as well as theoretical foundations for future research directions.