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Acute myeloid leukemia is a heterogeneous disease with a 5-year survival rate of 28.3%, and current treatment options constrained by dose-limiting toxicities. One of the key signaling pathways known to be frequently activated and dysregulated in AML is PI3K/AKT. Its dysregulation is associated with aggressive cell growth and drug resistance. We investigated the activity of Phenybutyl isoselenocyanate (ISC-4) in primary cells obtained from newly diagnosed AML patients, diverse AML cell lines, and normal cord blood cells. ISC-4 significantly inhibited survival and clonogenicity of primary human AML cells without affecting normal cells. We demonstrated that ISC-4-mediated p-Akt inhibition caused apoptosis in primary AML (CD34 +) stem cells and enhanced efficacy of cytarabine. ISC-4 impeded leukemia progression with improved overall survival in a syngeneic C1498 mouse model with no obvious toxic effects on normal myelopoiesis. In U937 xenograft model, bone marrow cells exhibited significant reduction in human CD45 + cells in ISC-4 (∼87%) or AraC (∼89%) monotherapy groups compared to control. Notably, combination treatment suppressed the leukemic infiltration significantly higher than the single-drug treatments (∼94%). Together, the present findings suggest that ISC-4 might be a promising agent for AML treatment.