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Chemo‐phototherapy has emerged as a promising approach to complement traditional cancer treatment and enhance therapeutic effects. However, it still faces the challenges of drug efflux transporter‐mediated chemoresistance and heat shock proteins (HSPs)‐mediated phototherapy tolerance, which both depend on an excessive supply of adenosine triphosphate. Therefore, manipulating energy metabolism to impair the expression or function of P‐glycoprotein (P‐gp) and HSPs may be a prospective strategy to reverse cancer therapeutic resistance. Herein, a chondroitin sulfate (CS)‐functionalized zeolitic imidazolate framework‐8 (ZIF‐8) chemo‐phototherapy nanoplatform (CS/ZIF‐8@A780/DOX NPs) is rationally designed that is capable of manipulating energy metabolism against cancer therapeutic resistance by integrating the photosensitizer IR780 iodide (IR780)‐conjugated atovaquone (ATO) (A780) and the chemotherapeutic agent doxorubicin (DOX). Mechanistically, ATO and zinc ions that are released in the acidic tumor microenvironment can lead to systematic energy exhaustion through disturbing mitochondrial electron transport and the glycolysis process, thus suppressing the activity of P‐gp and HSP70, respectively. In addition, CS is used on the surface of ZIF‐8@A780/DOX NPs to improve the targeting capability to tumor tissues. These data provide an efficient strategy for manipulating energy metabolism for cancer treatment, especially for overcoming cancer chemo‐phototherapy resistance.