Wnt signaling is involved in the regulation of cell proliferation, differentiation and apoptosis. Its aberrant activation is a key event in the pathogenesis and progression of human colorectal cancers. Dietary phytochemicals are gaining importance as chemotherapeutic agents owing to their potential to prevent, delay or reverse oncogenesis. Here we demonstrate that emodin (1,3,8-trihydroxy-6-methylanthraquinone), an anthraquinone present in the roots and bark of several medicinal plants, down regulates Wnt signaling pathway in human colorectal cancer cells (SW480 and SW620) by down regulating TCF/LEF transcriptional activity. Emodin significantly down regulated the expression of key players of Wnt signaling (β-catenin and TCF7L2) and also that of its various downstream targets (cyclin D1, c-Myc, snail, vimentin, MMP-2 and MMP-9). Two novel targets of emodin's action were discovered namely Wnt co-activator p300 (down regulated) and repressor HBP1 (up regulated). Morphological changes induced by emodin suggest mesenchymal to epithelial transition accompanied by the increase in E-cadherin expression in human colorectal cancer cells but a differentiation marker (alkaline phosphatase) was activated only in SW620 cells (metastatic origin) and not in SW480 cells (primary tumor-derived). Moreover, our data indicate that reactive oxygen species plays a key role in emodin-mediated down regulation of Wnt signaling as emodin-mediated inhibition of migration and induction of growth arrest were partially rescued by the reactive oxygen species scavenger ascorbic acid. Effects of emodin shown in this study may provide important insights for the use of this anthraquinone as a potential complementary and integrated medicine for the treatment of human colorectal cancer. © 2014 Elsevier B.V. All rights reserved.