Current therapies, including autologous CAR-T immunotherapy, fail to cure half of infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2Ar-ALL). Here we deploy allogeneic iNKT cells, ‘innately’ more powerful effectors than T cells, and equip them with CD19- and/or CD133-targeting CARs. We show that compared to mono-specific counterparts and bispecific CAR-T, CD19-CD133 bispecific CAR-iNKT not only have a more potent anti-leukemia activity, they are also able to eradicate medullary and leptomeningeal leukemia and induce sustained remissions without discernible hematologic toxicity. CAR-iNKT outperform CAR-T and target CAR antigen-negative/low leukaemia cells through a mechanism that requires dynamic, CAR- and CAR antigen-dependent upregulation of the activating innate receptor NKG2D and its engagement by its ligands in KMT2Ar-ALL cells. Thus, by engaging with two different types of leukemia-associated targets, CAR-iNKT provide a powerful platform for the treatment of KMT2Ar-ALL. This approach can be readily adapted for other high-risk malignancies, including those with otherwise difficult to target leptomeningeal involvement.