In our previous study, nonoxidized Fe in Fe@Au nanoparticles was found to play an essential role in the cancer-preferential cytotoxicity of Fe@Au in oral cancer models, in vitro and in vivo. Here, Fe@Au nanoparticles have demonstrated a similar, but less intensive, cytotoxicity in CRC cells. We found that the cytotoxicity of the nanoparticles was lower in particle CRC cells that were able to reduce their internal levels of Fe. Furthermore, the Au coatings significantly enhanced the cytotoxicity of nanoparticles in selected CRC cells. Therefore, both the Fe core and Au shell of Fe@Au are critical for the anticancer property observed in cancer cells.