Treating colorectal cancer (CRC) continues to be a clinical challenge. Coptisine, an alkaloid derived from Coptis chinensis Franch. shows toxic effects on CRC cells, but its underlying mechanism remains elusive. MFG-E8 is involved in tumor growth and progression. Herein, we evaluated the effects of coptisine on MFG-E8 in CRC, and explored the mechanism. The expression of MFG-E8 in CRC and adjacent normal colon tissue samples from patients was detected. The effects of coptisine on CRC cells HCT116 in vitro were evaluated by CCK-8, adhesion and transwell assays. A xenograft tumor model was used to assess the effects of coptisine in vivo. The morphology of CRC tissue was observed by HE staining. Cell signaling was tested using western blotting and immunohistochemical assay. The expression of MFG-E8 in human CRC tissue samples significantly increased compared with that of adjacent normal ones. Coptisine significantly reduced the expressions of MFG-E8 in HCT116 cells and tumor-bearing mice. Moreover, coptisine suppressed the growth, adhesion and metastasis of CRC cells. Coptisine also suppressed the expression of MMP-2 and MMP-9 via the PI3K/AKT signaling pathway. Furthermore, it inhibited epithelial-mesenchymal transition in vivo and in vitro. Coptisine inhibited CRC growth and progression by down-regulating MFG-E8, and is a potential candidate for treatment.