More than half of human colorectal cancers (CRCs) carry eitherKRASorBRAFmutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboringKRASorBRAFmutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolyticKRASorBRAFmutant cells leads to an energetic crisis and cell death not seen inKRASandBRAFwild-type cells. High-dose vitamin C impairs tumor growth inApc/KrasG12D mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations.