Bigelovin, a sesquiterpene lactone, has been demonstrated to induce apoptosis, inhibit inflammation and angiogenesis in vitro, but its potential anti-metastatic activity remains unclear. In the present study, two colon cancer mouse models, orthotopic tumor allografts and experimental metastatic models were utilized to investigate the progression and metastatic spread of colorectal cancer after bigelovin treatments. Results showed that bigelovin (intravenous injection; 0.3–3 mg/kg) significantly suppressed tumor growth and inhibited liver/lung metastasis with modulation of tumor microenvironment (e.g. increased populations of T lymphocytes and macrophages) in orthotopic colon tumor allograft-bearing mice. Furthermore, the inhibitory activities were also validated in the experimental human colon cancer metastatic mouse model. The underlying mechanisms involved in the anti-metastatic effects of bigelovin were then revealed in murine colon tumor cells colon 26-M01 and human colon cancer cells HCT116. Results showed that bigelovin induced cytotoxicity, inhibition of cell proliferation, motility and migration in both cell lines, which were through interfering IL6/STAT3 and cofilin pathways. Alternations of the key molecules including Rock, FAK, RhoA, Rac1/2/3 and N-cadherin, which were detected in bigelovin-treated cancer cells, were also observed in the tumor allografts of bigelovin-treated mice. These findings strongly indicated that bigelovin has potential to be developed as anti-tumor and anti-metastatic agent for colorectal cancer.