Background: Despite the rising 5-year survival rate of colorectal cancer (CRC) patients, the survival rate decreases as the stage progress, and a low survival rate is highly associated with metastasis. Purpose: The purpose of our study is to investigate the effect of dehydroevodiamine (DHE) on the lung metastasis of CRC and the proliferation of CRC cells. Study design: Cell death was confirmed after DHE treatment on several CRC cell lines. The mechanism of cell cytotoxicity was found using flow cytometry. After that, the expression of the proteins or mRNAs related to the cell cytotoxicity was confirmed. Also, anti-metastatic ability of DHE in CRC cells was measured by checking the expression of Epithelial to Mesenchymal Transition (EMT) markers. Lung metastasis mouse model was established, and DHE was administered orally for 14 days. Results: DHE suppressed the viability of HCT116, CT26, SW480, and LoVo cells. DHE treatment led to G2/M arrest via a reduction of cyclin B1/CDK1 and caspase-dependent apoptosis. It also induced autophagy by regulating LC3-II and beclin-1 expression. Additionally, migration and invasion of CRC cells were decreased by DHE through regulation of the expression of EMT markers. Oral administration of DHE could inhibit the lung metastasis of CT26 cells in an in vivo model. Conclusion: Our study demonstrated that DHE has a potential therapeutic effect on colorectal cancer metastasis.