Few targeted drugs were approved for treatment of colorectal cancer (CRC). Cyclin-dependent kinase 8 played a vital role in regulating transcription and was a key colorectal oncogene associated to colorectal cancer. Here, through de novo drug design and in depth structure-activity relationship analysis, title compound <b>22</b>, (3-(3-(1<i>H</i>-pyrrolo[2,3-<i>b</i>]pyridin-5-yl)phenyl)-<i>N</i>-(4-methyl-3-(trifluoromethyl)phenyl)propenamide), was discovered as a potent type II CDK8 inhibitor, which exhibited potent kinase activity with an IC<sub>50</sub> value of 48.6 nM and could significantly inhibit tumor growth in xenografts of CRC in vivo. Further mechanism studies indicated that it could target CDK8 to indirectly inhibit β-catenin activity, which caused downregulation of the WNT/β-catenin signal and inducing cell cycle arrest in G2/M and S phases. More importantly, the title compound exhibited low toxicity with good bioavailability (<i>F</i> = 39.8%). These results could provide the reference for design of new type II CDK8 inhibitors against colorectal cancer.