Lunasin is a bioactive peptide originally isolated from soybean and has demonstrated chemopreventive and anti-cancer properties against skin, colon and breast cancers. The objective of the study was to evaluate the capability of intraperitoneally and orally-administered soybean-derived peptide lunasin to inhibit KM12L4 human colon cancer cell metastasis in a mouse model. Intraperitoneal (i.p.) injection of lunasin (4 mg/kg bw/day) reduced the number of liver metastasis by 50% (P = 0.047) and the liver weight/body weight ratio by 23% (P = 0.039). Oral administration of lunasin reduced the number of liver metastasis by 56% (8 mg/kg bw/day, P = 0.293) and 94% (20 mg/kg bw/day, P = 0.247). Immunohistochemical staining of the liver-tissue section showed that lunasin at 20 mg/kg bw dose did not significantly reduce the expression of proliferating cell nuclear antigen, increased the expression of proapoptotic Bax by 2.7-fold but also increased the expression of the antiapoptotic Bcl-2 by 3.8-fold. Regarding epigenetic markers, H3K18 was not significantly affected by either oral dose while H4K8 was dose dependently increased by 2.3-fold (P = 0.001, 8 mg/kg bw) and 2.7-fold (P < 0.001, 20 mg/kg bw). On the other hand, i.p. injection of lunasin reduced both histone acetylation markers significantly. The difference on the effects can be attributed to the different routes of administration used leading to digestion of lunasin when given by oral gavage. In conclusion, lunasin reduced colon cancer metastasis in vivo; however, more studies are needed to determine the oral dose of lunasin and prevent colon cancer metastasis.