AML is a kind of hematological malignant tumor that urgently requires different treatment options in order to increase the cure rate and survival rate. Cytarabine (ara-C) is currently the main drug used to treat AML patients and is usually combined with different chemotherapeutic agents. However, due to resistance to ara-C, a new combination is needed to reduce ara-C resistance and improve treatment outcome. As is known to all, ginseng is a traditional Chinese herb; compound K is the principal metabolic product of ginsenoside which also has anti-cancer activity in some cancer cells, while the mechanism is unclear. In our previous study, we found that compound K inhibited AML cell viability and induced apoptosis, and compound K combined with ara-C synergistically induced AML cell proliferation arrest. Thus, we sought to investigate the reason for this by focusing on the mitochondrial dysfunction and DNA damage. In this paper, our results provide a foundation for the clinical evaluation of concomitant administration of compound K and ara-C in order to reduce the resistance to ara-C and improve AML treatment.