A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action PtIV prodrugs. The dual targeting was established by liposomal encapsulation of PtIV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of the drug‐loaded liposomes in the tumor. After the release of the PtIV prodrug inside cancer cells, a second stage of targeting directed a portion of the PtIV prodrugs to the mitochondria. Upon intracellular reduction, these PtIV prodrugs released two bioactive molecules, acting both on the mitochondrial and on the nuclear DNA. Our PtIV system showed excellent activity in vitro and in vivo, characterized by a cytotoxicity in a low micromolar range and complete tumor remission, respectively. Notably, marked in vivo activity was accompanied by reduced kidney toxicity, highlighting the unique therapeutic potential of our novel dual‐targeting dual‐action platform. Ministry of Education (MOE) Accepted version G.P. acknowledges the National University of Singapore (NUS) for financial support (grant C-141-000-097-001). W.H.A. acknowledges the Ministry of Education Singapore (MOE) for financial support (grant R143000680114). D.G acknowledges the support of the Israel Science Foundation (grant 1611/14) and the support of the Alex Grass Center for Drug Design and Synthesis.Y.Z. acknowledges the Depart- ment of Pharmacy (NUS) and Hebrew University of Jerusa- lem (HUJ) for the research scholarship for ajoint PhD degree.M.V.B.acknowledges E. Fasolko and T. Hajsz for generating the artwork.