Levels of JMJD2D were significantly higher in human colorectal tumors than in control tissues and correlated with levels of proliferating cell nuclear antigen. JMJD2D knockdown reduced CRC cell proliferation, migration, and invasion as well as growth of xenograft tumors and formation of metastases in mice. JMJD2D was required for expression of beta-catenin in CRC cell lines; ectopic expression of JMJD2D increased the promoter activities of genes regulated by beta-catenin (MYC, cyclin D1, MMP2, and MMP9). We found that JMJD2D and beta-catenin interact physically, and JMJD2D demethylated H3K9me3 at promoters of beta-catenin target genes. JMJD2D-knockout mice developed fewer colitis-associated colorectal tumors than control mice and their tumor tissues had lower levels of beta-catenin, MYC, cyclin D1, and proliferating cell nuclear antigen than tumors from control mice. Apcmin/+;Jmjd2d–/– mice developed fewer and smaller colon tumors than Apcmin/+ mice. Mice given 5-c-8HQ developed smaller and fewer colitis-associated tumors, with lower levels of cell proliferation, than mice given vehicle. Apcmin/+ mice given 5-c-8HQ also developed fewer tumors in intestines and colons than mice given vehicle.