Through a comprehensive assessment of stability, tumor targeting, and safety, we identified the optimal NQO1‐responsive DON prodrug, 10e, a molecule that demonstrated potent antitumor activity in diverse ex vivo and in vivo scenarios and exceeded the efficacy of the clinical phase II drug, DRP104, in the Osimertinib‐resistant malignant tumor model. Here, NQO1 is linked to cancer.