Mutations in isocitrate dehydrogenase 2 (IDH2) have been noted to impact cellular differentiation in addition to DNA and histone methylation. However, little is known about the impact of IDH2 mutations on intracellular signaling. Using an isogenic cell line model, we investigated both differentiation and signaling responses in IDH2 mutant cells and show augmented responses to inflammatory immune ligands. Using phospho-specific flow and mass cytometry, we demonstrate IDH2 mutant cells were significantly more sensitive to IL-1β at multiple downstream readouts. Further, bulk RNA sequencing confirmed increases in cytokine-related signaling pathways and NF-κB target genes. Single-cell RNA sequencing of unstimulated and stimulated cells confirmed altered IL-1β transcriptional responses in the IDH2 mutant cells. Targeted inhibition of the IKK complex reduced IL-1β responses and induced cell death in primary IDH-mutated leukemia samples. Together, these results confirm altered IL-1β signaling in IDH2 mutant cells and identify this pathway as a potential therapeutic target.