In order to reverse drug resistance and reduce side effects of oxaliplatin (OXA) in colon cancer (CRC) treatment, six platinum(IV) complexes modified with indole–chalcone derivatives were synthesized and evaluated for their antiproliferative activities against various CRC cell lines. Among them, indole–chalcone oxaliplatin(IV)-propanoate (ICplatin-18), which obtained a two-methylene linker and was derived from oxaliplatin(IV), exhibited the most parental anticancer activity compared with either monotherapy or combination against parent and OXA-resistant HCT-116 (HCT-116/OXA) cells, obtained good selectivity toward normal cell line (L02 and HUEVC), and significantly inhibited migration of HCT-116 cells. This performance may be associated to the dramatic increase in intracellular accumulation and enhancement of DNA damage. Further mechanistic studies indicated that ICplatin-18 significantly inhibited tubulin polymerization, elevated accumulation of intracellular reactive oxygen molecule, and activated mitochondrial apoptotic.