The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria‐targeted rhenium(I) complex (DFX‐Re3), integrating the clinical iron chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications, DFX‐Re3 can elevate the methylation levels of histone, DNA, and RNA. As a consequence, DFX‐Re3 affects the events related to apoptosis, RNA polymerases, and T‐cell receptor signaling pathways. Finally, it is shown that DFX‐Re3 induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis. Reported here is a mitochondria‐targeted ReI complex, DFX‐Re3, that can relocate iron to the mitochondria and change the metabolites related to epigenetics. DFX‐Re3 can elevate the methylation levels of histone/DNA/RNA, affect RNA polymerase activities, and induce immunogenic apoptosis. This study provides a new approach to the design of epigenetic drugs for recoding the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.