Aberrant activation of Homeobox genes in human cancers has long been documented, whereas the mechanisms underlying remain largely obscure. Super-enhancers (SEs) act as key regulatory elements for both cell identity genes and cancer genes. Herein, we reported that SE-associated HOXB gene cluster represented a common feature of colorectal cancer (CRC) cell lines and multiple HOXB genes within this cluster were overexpressed in CRC. Among them, we found that HOXB8 was oncogenic and its activation in CRC was driven by SE instead of genetic alteration. We further demonstrated that the master transcription factor MYC preferentially occupied SEs over TEs (typical enhancers) and regulated HOXB8 transcription by binding to the active elements of its SE. HOXB8 silencing induced reversal of transcriptional signatures associated with malignant phenotypes of CRC. Mechanistically, HOXB8 interacted with a key metastasis regulator BACH1 and instigated BACH1-mediated transcriptional cascade by directly occupying and activating BACH1 gene transcription together with BACH1 itself. Lastly, the relevance of HOXB8 activation in clinical settings was strengthened by its close association with prognostic outcomes of CRC patients.