This review provides an updated overview of the role of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia. It highlights the significant progress made over the past three decades, particularly following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The article discusses the activation and inhibition mechanisms of the JAK/STAT pathway, its involvement in both de novo and secondary leukemias, and the crosstalk between the JAK/STAT pathway and the p53 pathway. It also explores the development and clinical applications of JAK/STAT inhibitors, including their mechanisms of action, efficacy, and safety in treating leukemia. The review concludes by discussing the potential of combination therapies involving JAK/STAT inhibitors and other drugs, as well as the ongoing research and future directions in this field.This review provides an updated overview of the role of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in leukemia. It highlights the significant progress made over the past three decades, particularly following the identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPNs). The article discusses the activation and inhibition mechanisms of the JAK/STAT pathway, its involvement in both de novo and secondary leukemias, and the crosstalk between the JAK/STAT pathway and the p53 pathway. It also explores the development and clinical applications of JAK/STAT inhibitors, including their mechanisms of action, efficacy, and safety in treating leukemia. The review concludes by discussing the potential of combination therapies involving JAK/STAT inhibitors and other drugs, as well as the ongoing research and future directions in this field.