More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25-50% of patients respond to standard-of-care therapies， response duration is typically short， and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors， such as venetoclax， are promising therapies for AML. Nonetheless， resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models ， and . Alvocidib decreased MCL-1， and/or increased pro-apoptotic proteins such as BIM or NOXA， often synergistically with venetoclax. Over-expression of BCL-XL diminished synergy， while knock-down of BIM almost entirely abrogated synergy， demonstrating that the synergistic interaction between alvocidib and venetoclax is primarily dependent on intrinsic apoptosis. CDK9 inhibition predominantly mediated venetoclax sensitization， while CDK4/6 inhibition with palbociclib did not potentiate venetoclax activity. Combined， venetoclax and alvocidib modulate the balance of BCL-2 family proteins through complementary， yet variable mechanisms favoring apoptosis， highlighting this combination as a promising therapy for AML or high-risk MDS with the capacity to overcome intrinsic apoptosis mechanisms of resistance. These results support clinical testing of combined venetoclax and alvocidib for the treatment of AML and advanced MDS.