Chemodynamic therapy (CDT) based intracellular chemical reactions to produce highly cytotoxic reactive oxygen species has received wide attention. However, low efficiency of single CDT in weakly acidic pH and glutathione (GSH) overexpressed tumor cells has limited its clinical application. For this study were prepared two-dimensional metal-organic framework (MOF) to improve CDT efficiency based on the combined action of bimetallic CDT, consumption of overexpressed glutathione (GSH) in cells, folic acid (FA) induced tumor targeting and triphenylphosphine (TPP) induced mitochondrial targeting. With the use of Cu(II) as the central ion and tetrakis(4-carboxyphenyl)porphyrin (TCPP) as the ligand, two-dimensional Cu-MOF nanosheets were prepared, which were surface modified by manganese dioxide based on the redox reaction between poly(allylamine hydrochloride) (PAH) and KMnO to obtain Cu-MOF@MnO. Then FA and TPP were coupled with the nanosheets to form the title nanoplatform. Comprehensive physiochemical research has suggested that Cu(II) and MnO constituents in the nanoplatform could consume intracellular GSH and hydrogen peroxide to generate hydroxyl radicals through a Fenton-like reaction; meanwhile Cu(II) could undergo a Russell reaction to produce cytotoxic singlet oxygen. Detailed and biological experiments have revealed a good biosafety profile and a high tumor suppression effect. Therefore, the present research has realized multiple and efficient CDT effects with the aid of the sequential targeting of FA/TPP, also providing a strategy for the development of CDT drugs based on polymetallic organic frameworks.