Icraiin (ICA) is a flavonoid glucoside derived from the Epimedium plant genus, which has potent regenerative properties and is used in western medicine to treat impotence. Recently, ICA has generated great interest in improving hepatic stellate cell function and cardiac rejuvenation. However, how this natural component functions in hematopoiesis remains unexplored. Here we have examined the role of ICA on hematopoietic stem cells (HSCs) using the cancer-prone disease model of Fanconi anemia (FA), an inherited bone marrow failure syndrome with extremely high risk of leukemic predisposition. We show that ICA reverses the less quiescent status of HSCs deficient for the Fanca or Fancd2 gene, and improves the ability of these mutant stem cells to form colony formation units (CFU) in vitro and reconstitutes hematopoiesis in transplanted recipients. Further analysis reveals that ICA upregulates enzyme activity of the chromatin binding protein SIRT6 in Fanca-/- and Fancd2-/- HSCs, both of which have an intrinsic low SIRT6 activity. Furthermore, forced expression of SIRT6 blocks the natural decline of quiescent HSCs in Fanca-/- or Fancd2-/- mice and improves the repopulating capacity of these mutant HSCs in irradiated recipients. Mechanistically, ICA enhances SIRT6-mediated H3K9 deacetylation on the promoter of NF-κB and represses the expression of NF-κB target genes. Together, our findings indicate that ICA improves the function of HSCs by stimulating SIRT6 activity and contributes to the regenerative effect of ICA.