Increasing evidence highlight tachykinin receptors as a prominent player in hematological malignancy. We previously revealed the proto-oncogenic role of neurokinin-1 receptor (NK-1R) in acute myeloid leukemia (AML),1 whereas the role of neurokinin-2 receptor (NK-2R) has not been elucidated. Herein, we found NK-2R was significantly up-regulated in AML patients in The Cancer Genome Atlas databases. This result was further confirmed in blood from AML patients and a range of human leukemia cells. Then, we verified that blocking NK-2R by SR48968 markedly promoted cell death in human myeloid leukemia without cytotoxicity to normal cells. Mechanically, we uncovered that SR48968 induced cytotoxicity through necroptosis mediated by calcium overload-driven reactive oxygen species (ROS) accumulation. In summary, our results propose that NK-2R antagonist SR48968 may be used as a new therapeutic approach for myeloid leukemia.