Engineering functional nanomaterials to have both high therapeutic efficacy and minimal side‐effects has become a promising strategy for next‐generation cancer treatments. Herein, an adenosine triphosphate (ATP) depletion and reactive oxygen species‐enhanced combination chemotherapy platform is introduced whereby therapeutic samarium (Sm³⁺) ions and (−)‐epicatechin (EC) are integrated via a metal‐phenolic network (Sm^III‐EC). The independent pathway between Sm³⁺ and EC can achieve a synergistic therapeutic effect through the mitochondrial dysfunction process. Sm^III‐EC nanoparticles cause a significant reduction of viability of C26 murine colon carcinoma cells while with lower systemic toxic effects on normal cell lines. Sm^III‐EC nanoparticles are used to directly compare with a clinic anticancer drug 5‐fluorouracil. Sm^III‐EC nanoparticles not only decrease the tumor volume but also do not affect the body weight of mice and normal organs, showing significant advantages over clinic counterpart. These facts suggest that Sm^III‐EC nanoparticles represent a clinically promising candidate for colon cancer treatment with a targeted therapeutic effect and minimum side toxicity.