Leukemia is a clonal malignant disease originating abnormal hematopoietic stem cells or progenitor cells. The key issue of leukemia treatment is its drug-resistance. SIRT3 is the main mitochondrial NAD+ dependent deacetylase. It regulates enzymes and transcription factors of many metabolism pathways. SIRT3 acts both as oncogenic gene and tumor-suppressing gene in the oncogenesis of different cancers. Studies have shown that reactive oxygen species (ROS) level is closely related to drug resistance of cancer cells. ROS level is elevated in leukemia cells, thus affecting its drug resistance. SIRT3 can downregulate ROS level in many ways and enhance cell survival in the case of oxidative stress. Decreased deacetylase activity of SIRT3 makes leukemic cells more vulnerable to oxidative stress so that they are more sensitive to current chemotherapies. Through discovering the function of SIRT3 in leukemia cells, a chance of finding a new target for leukemia treatment can be found. This article reviews recent advances on the role of SIRT3 in leukemia drug resistance.