The dysregulation of transcription factors has an important impact on the oncogenesis and tumor progression. Nonetheless, its functions in colorectal cancer metastasis are still unclear. In this study, four transcription factors (HNF4A, HSF1, MECP2 and RAD21) were demonstrated to be associated with the metastasis of colorectal cancer in both RNA and protein levels. To comprehensively explore the intrinsic mechanisms, we profiled the molecular landscape of these metastasis-related transcription factors from multiple perspectives. In particular, as the crucial factors affecting genome stability, both copy number variation and DNA methylation exerted their strengths on the expression of these transcription factors (except MECP2). Additionally, based on a series of bioinformatics analyses, putative long non-coding RNAs were identified as functional regulators. Besides that, rely on the ATAC-Seq and ChIP-Seq profiles, we detected the target genes regulated by each transcription factor in the active chromatin zones. Finally, we inferred the associations between the target genes by Bayesian networks and identified LMO7 and ARL8A as potential clinical biomarkers. Taken together, our research systematically characterized the regulatory cascades of HNF4A, HSF1, MECP2 and RAD21 in colorectal cancer metastasis.