The study aims to investigate the effect of microRNA-497 (miR-497) expression and bufalin treatment in regulating colorectal cancer invasion and metastasis. The expression of miR-497 in colorectal cancer cells with prior treatment with bufalin was determined using real-time quantitative PCR. The nude mouse abdominal aortic ring assay and the human umbilical vein endothelial cell (HUVEC) migration assays were used to measure the angiogenic effect of bufalin. The effect of both bufalin treatment and miR-497 overexpression on colorectal cancer metastasis was measured using an animal tumor model together with in vivo imaging. These results suggested: (1) In the HCT116 cells and HUVECs, proliferation was inhibited in a time-dependent and/or concentration-dependent manner following the administration of bufalin; (2) Bufalin inhibited cell migration in a concentration-dependent manner by cell motility assays; (3) In the aortic ring assay, administration bufalin to the aortic ring significantly promoted micro-angiogenesis of nude mouse abdominal aorta in a concentration-dependent and time-dependent manner; (4) miR-497 was upregulated in human colorectal cancer HCT116 cells treated with different concentrations of bufalin in a concentration-dependent manner; and (5) Combined application of bufalin and miR-497 significantly reduced metastatic lesions and reduced weight loss compared with bufalin alone and control groups in vivo. This study revealed that bufalin inhibited angiogenesis and regulated miR-497 expression and that bufalin and miR-497 acted in synergy to inhibit colorectal cancer metastasis, resulting in improved quality of life in a nude mouse model.