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KMT2A-rearranged (KMT2A-r) acute leukemias are especially prevalent in the pediatric population. KMT2A-fusion proteins drive leukemogenic gene expression through an interaction with a chromatin complex that includes the scaffold protein menin, giving rise to aggressive acute leukemias. RAS pathway mutations are also common in pediatric leukemia. In a cohort of 1750 patients enrolled on Children's Oncology Group (COG) trials, we identified RAS pathway mutations in 43% of acute myeloid leukemia (AML) cases. The presence of RAS pathway mutations in KMT2A-r AML was associated with a lower complete remission rate, poor event-free survival and overall survival (OS), and early relapses. Given the inferior outcome observed for children with dual mutations, we next sought to identify efficacious targeted drug combinations for this subset of childhood leukemia. We evaluated RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib in combination with the menin inhibitor revumenib. Treatment of AML cell lines and cultured leukemia cells from patient-derived xenograft (PDX) models resulted in a synergistic decrease in viability and promoted cell cycle arrest, apoptosis, and downregulation of Myc targets in the combination compared with each drug alone. In vivo, the combination treatment of AML pediatric PDX models harboring KMT2A-r and RAS mutations reduced leukemia burden compared with single-drug treatments but without improving OS compared with menin inhibition alone. Our preclinical study suggests a potential targeted treatment combination for KMT2A-r and RAS pathway-mutant leukemia but one that will require further optimization. These trials were registered at as NCT00070174, NCT00372593, NCT01371981, and NCT00002798.