The molecular mechanism underlying cancer invasiveness and metastasis of colorectal cancer (CRC) remains elusive. Here we reported a strong correlation of the levels of neuregulin receptor degradation protein-1 (Nrdp1) and matrix metalloproteinase-7 (MMP7) in CRC from the patients. We then used a human CRC line, Caco-2, to study the underlying molecular basis. We found that Nrdp1 inhibited the phosphorylation of ErB3, a key player in epidermal growth factor receptor (EGFR) signaling in Caco-2 cells, which is required for activation of MMP7 to promote cell invasion. Our findings thus reveal Nrdp1, EGFR signaling, and MMP7 as promising therapeutic targets for preventing the metastasis of CRC.