Cadmium (Cd) is a toxic heavy metal that impairs the development of hematopoietic stem cells (HSCs) in mice, yet the mechanism of how Cd influences HSC remains elusive. Herein, we show that Cd activated non-canonical Wnt signaling pathway to impair HSC function in mice. After exposure to 10 ppm Cd chloride (CdCl2) via drinking water for 3 months, C57BL/6 mice displayed aberrant HSC function, in that HSC from Cd-treated mice were less efficient in rescue of lethally irradiated hosts and less competitive under mixed chimeric condition. Further analyses indicated that the small GTPase cdc42 was activated and its distribution pattern was depolarized in HSC by Cd exposure, and inhibition of cdc42 by casin, a selective chemical inhibitor, recovered the HSC capacity in rescue assay and their potential for lymphopoiesis under competitive mixed chimeric assay. Cd interaction with HSC was sufficient to promote noncanonical Wnt signaling pathway, but not canonical Wnt signaling pathway, to drive cdc42 activation and further increase the expression of C/EBPα and decrease the expression of Hhex. Moreover, Cd-induced activation of non-canonical Wnt signaling pathway in HSC did not persist long-termly in the presence of a normal niche without Cd, in that the elevated non-canonical Wnt signaling by Cd was diminished in HSC in the BM of normal recipients receiving purified HSC from Cd-treated mice after 6 months posttransplantation. Taken together, our study suggests that Cd activates cdc42 of noncanonical Wnt signaling pathway to impair HSC function, a previously unknown mechanism for Cd toxicity on HSC.