Following the success of natural compounds for treating solid tumors, interest in applying such agents for treating hematologic malignancies has been fired up more strikingly. Thus far, anti-leukemic effects of several compounds have been examined in different leukemia cell lines, especially in acute lymphoblastic leukemia. The agent that has recently attracted tremendous attention is Britannin, which is derived from Inula aucheriana DC., a plant that grows in Iran (Azerbaijan) and Türkiye. In this study, we evaluated the effects of this compound in myeloid leukemia for the first time.We treated chronic myeloid leukemia (CML)-derived K562 and acute myeloid leukemia (AML)-derived U937 cells with different concentrations of britannin. We used several assays, including trypan blue, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, bromodeoxyuridine/5-bromo-2'-deoxyuridine, flow cytometry, and quantitative real-time polymerase chain reaction analysis, to study anti-leukemic effects of the compound.Our results show that while britannin remarkably reduced the survival of both cell lines in a concentrations-dependent manner, it had cytotoxic effects neither on mouse fibroblast-derived L929 cells nor on normal peripheral mononuclear cells. Moreover, among the tested cell lines, the viability of CML-derived K562 cells was inhibited at higher concentrations of the compound compared with AML-derived U937 cells. We found that britannin induced apoptotic cell death in both cell lines by altering the expression of anti- and pro-apoptotic genes. Britannin also hampered proliferative capacity of the cells in a p21/p27-dependent manner.Overall, we suggest that based on the lack of toxicity on the normal cells and valuable anti-leukemic activities, britannin could be a promising agent in the treatment strategies of both CML and AML. However, further investigations must more precisely study this compound's mechanism of action and evaluate its safety profile.