Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular hydrogen peroxide (H2O2) into hydroxyl radicals (OH•). Although many studies on H2O2 supplementation have been conducted to improve the therapeutic effect of CDT, few studies have focused on the application of superoxide radical (O2−•) in CDT, which may result in better efficacy. A major concern about O2−•‐mediated CDT is its tendency to induce serious oxidative damage to normal tissues, which may be addressed by using a degradable O2−• scavenger. Here, a harmless‐harmful switchable and uninterrupted laccase (LAC)‐instructed killer (HULK) is constructed, which is the first CDT agent accelerated by LAC‐instructed O2−• generation and possesses a harmless‐harmful switchable effect because of the photodegradation of the O2−• scavenger iron‐chlorin e6 (FeCe6). LAC‐instructed substrate oxidation effectively catalyzes O2−• production with the help of intracellular reduction, thereby promoting the conversion of Fe3+ to Fe2+, accelerating the generation of OH•, and inducing tumor cell apoptosis and necrosis. The introduced O2−• scavenger FeCe6 is quickly photodegraded during irradiation, while LAC‐instructed O2−• generation proceeds as before, resulting in activatable CDT. This work not only provides the first strategy for LAC‐instructed O2−• generation but also presents new insight into activatable CDT. A harmless–harmful switchable and uninterrupted laccase (LAC)‐instructed killer (HULK) is designed as a chemodynamic therapy (CDT) agent, which is the first CDT agent accelerated by LAC‐instructed superoxide radical (O2−•) generation and possesses harmless–harmful switchable effect because of the photodegradation of O2−• scavenger Fe‐chlorin e6, showing great potential as a safe and effective CDT agent.