By analysing the database and our clinical specimens, knockout of FBXL8, as well as immunoprecipitation and in vivo experiments, we found that FBXL8 was significantly up‐regulated in CRC and promoted CRC cell proliferation, migration and stem‐like properties through ubiquitination degradation of the tumour suppressor gene p53. This evidence concerns the gene FBXL8 and colorectal carcinoma.