TP53 mutation is a frequent tumor suppressor mutation and a critical prognostic indicator across studies in many malignant tumors including hematologic malignancies. However, the role of TP53 and its correlative pathway in acute myeloid leukemia (AML) is enigmatic, which may provide possible emerging strategies with the potential to improve outcomes in AML. Accordingly, we focus not only on the TP53 mutation but also on the underlying mechanisms of the mutated TP53 signal pathway. While it is now generally accepted that TP53 mutations are widely associated with a dismal prognosis, resistance to chemotherapy, and high incidence of relapse and refractory AML. Hereby, the current therapeutics targeting TP53 mutant AML are summarized in this review. This will address emerging TP53-based therapeutic approaches, facilizing the TP53-targeted treatment options.