Licochalcone A (LicA), a major phenolic constituent of licorice, has antiproliferative and anti-inflammatory properties in human and murine cell lines. We previously showed that LicA down-regulates the expression of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) via the modulation of nuclear factor-kappaB and activator protein-1 activation in cell culture. We therefore tested whether LicA inhibits carcinogenesis and metastasis in mouse models. To induce colon carcinogenesis, C57BL/6 mice were given a single intraperitoneal injection of azoxymethane (10 mg/kg body weight), followed by 1% dextran sulfate sodium in the drinking water. Additionally, we also assessed the effect of LicA on liver metastasis by intrasplenic injection of BALB/c mice with CT-26 cells. Feeding the mice with LicA (5, 15, and 30 mg/kg body weight) significantly reduced tumor formation as well as the number of cells expressing proliferating cell nuclear antigen, beta-catenin, COX-2, and iNOS in the colon. LicA also decreased colon levels of proinflammatory cytokines and chemokines. In addition, LicA significantly increases survival of animals and inhibited liver metastasis as well as the expression of matrix metalloproteinase-9 in the liver. These preclinical studies indicate that LicA has potent antitumor and antimetastatic activity, suggesting that LicA could increase efficacy and improve patient outcomes in colorectal cancer.