The up-regulation of ALL1-fused gene from chromosome 1q (AF1q) is commonly seen in aggressive hematologic malignancies as well as in several solid tumor tissues. However, its expression and intrinsic function in human colorectal cancer (CRC) remains largely undefined. To explore the role of AF1q in human CRC progression, AF1q expression was analyzed in human CRC tissue samples and CRC cell lines. Clinical specimens revealed that AF1q was up-regulated in human CRC tissues, and that this up-regulation was associated with tumor metastasis and late tumor, lymph node, metastasis (TNM) stage. AF1q knockdown by shRNA inhibited tumor cell proliferation, migration, invasion, and epithelial-mesenchymal transition in vitro, as well as tumorigenesis and liver metastasis in vivo, whereas these effects were reversed following AF1q overexpression. These AF1q-mediated effects were modulated by the protein kinase B (AKT) signaling pathway, and inhibition of AKT signaling attenuated AF1q-induced tumor promotion. Thus, AF1q contributes to CRC tumorigenesis and progression through the activation of the AKT signaling pathway. AF1q might therefore serve as a promising new target in the treatment of CRC.