Acute myeloid leukemia (AML) results from the enhanced proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Using an ex vivo functional screening assay, we identified that the combination of the BTK inhibitor ibrutinib and BCL2 inhibitor venetoclax (IBR + VEN), currently in clinical trials for chronic lymphocytic leukemia (CLL), demonstrated enhanced efficacy on primary AML patient specimens, AML cell lines, and in a mouse xenograft model of AML. Expanded analyses among a large cohort of hematologic malignancies (n = 651 patients) revealed that IBR + VEN sensitivity associated with selected genetic and phenotypic features in both CLL and AML specimens. Among AML samples, 11q23 MLL rearrangements were highly sensitive to IBR + VEN. Analysis of differentially expressed genes with respect to IBR + VEN sensitivity indicated pathways preferentially enriched in patient samples with reduced ex vivo sensitivity, including IL-10 signaling. These findings suggest that IBR + VEN may represent an effective therapeutic option for patients with AML.