Acute myeloid leukemia (AML) is an aggressive hematological malignancy with limited treatment options. Inflammation is often a contributing factor to the development and progression of AML, and related diseases, and can potentiate therapy failure. Previously, we had identified anti-inflammatory roles and anti-AML efficacy for blueberry extracts. The present study extended these observations to determine that the polyphenol quercetin inhibited neutral sphingomyelinase (N-SMase) activity and exerted anti-AML efficacy. Moreover, quercetin was shown to exert combinatorial anti-AML efficacy with nanoliposomal ceramide. Overall, this demonstrated that quercetin could block the pro-inflammatory actions of N-SMase and augment the efficacy of anti-AML therapeutics, including ceramide-based therapeutics.