In this study, we demonstrated that niclosamide, a well-tolerated FDA-approved oral anthelminthic drug, selectively blocked CREB activation, disrupted CREB-CBP interaction, and inhibited CREB-driven genes expression, resulting in inhibition of AML cell viability in vitro and leukemia progression in AML-PDX mice. Here, CREBBP is linked to acute myeloid leukemia.