Our study suggests that FBXL8 is up‐regulated in CRC and reduces the stability of p53 by binding to SCF components through its Fbox region and by binding to p53 through its LRR region to promote the ubiquitination of p53, thereby contributing to the pathological mechanism of CRC by promoting cell proliferation, migration and stem‐cell‐like properties. Here, TP53 is linked to colorectal carcinoma.