Acute myeloid leukemia (AML) is an aggressive hematological malignancy that gradually develops resistance to current chemotherapy treatments. The available chemotherapy drugs show serious non-specific cytotoxicity to healthy normal cells, resulting in relapse and low survival rates. Natural small molecules with less toxicity and high selectivity for AML are urgently needed. In this study, we confirmed that pyridoxine (vitamin B6) selectively induces monocyte macrophages to undergo programmed cell death in two different modes: caspase-3-dependent apoptosis in U937 cells or GSDME-mediated pyroptosis in THP-1 cells. Further molecular analysis indicated that blocking the caspase pathway could switch the death to MLKL-dependent necroptosis and subsequent extensive inflammatory response. Pyridoxine also delayed the disease progression in a THP-1 leukemia mouse model. In addition, it induced the death of primary AML cells from AML patients by activating caspase-8/3. Overall, our results identify pyridoxine, a low-toxicity natural small molecule, as a potential therapeutic drug for AML treatment.Copyright © 2020. Published by Elsevier B.V.