Although ΔNp63 is known to promote cancer cell proliferation, the underlying mechanism behind its oncogenic function remains elusive. We report here a functional interplay between ΔNp63 and Δ133p53. These two proteins are co-overexpressed in a subset of human cancers and cooperate to promote cell proliferation. Mechanistically, Δ133p53 binds to ΔNp63 and utilizes its transactivation domain to upregulate GLUT1, GLUT4, and PGM expression driving glycolysis. While increased glycolysis provides cancer cells with anabolic metabolism critical for proliferation and survival, it can be harnessed for selective cancer cell killing. Indeed, we show that tumors overexpressing both ΔNp63 and Δ133p53 exhibit heightened sensitivity to vitamin C that accumulate to a lethal level due to accelerated uptake via overexpressed GLUT1. These observations offer a new therapeutic avenue that could be exploited for clinical applications.