Significance Deregulated global mRNA translation is a feature of various cancers and considered important in oncogenic transformation. In colorectal cancer (CRC), the role of the most common driver mutations in APC , KRAS , SMAD4 , and TP53 on the global translational capacity are incompletely understood. Here, using mouse and human intestinal organoids, we found that each mutation governs the global translational capacity of the epithelial cell. Global translation is linked to known oncogenic hallmarks, including cell proliferation and growth upon accumulation of these mutations, posing the translational apparatus as a potential therapeutic target in CRC.