In summary, we demonstrated that FOXO4 has a tumor-suppressor role that could inhibit EMT, migration, and in vivo metastasis in colorectal cancer by regulating the APC2/β-catenin axis, which revealed the function and mechanism of FOXO4 in colorectal cancer, providing a potential therapeutic strategy for patients with CRC. The gene discussed is APC2; the disease is colorectal carcinoma.