Public transcriptome databases provide a valuable resource for genome‑wide co‑expression network analysis and investigation of the molecular mechanisms that underlie pathogenesis. To discover genes that may affect patient survival, a large‑scale analysis of human colorectal cancer (CRC) datasets that were retrieved from the NCBI Gene Expression Omnibus was performed. A gene co‑expression network was constructed using weighted gene co‑expression network analysis (WGCNA). A total of 18 co‑expressed gene modules were identified, of which two genes corresponded to cell migration and the cell cycle, two genes were involved in immune responses, two genes corresponded to mitochondrial function, and one gene corresponded to RNA splicing. A total of eight hub genes in the cell migration/extracellular matrix module were associated with poor prognosis in CRC, and the P‑value for collagen type VI α3 chain (COL6A3) was the lowest. In silico analysis of cell type‑specific gene expression and COL6A3 knockout experiments indicated the clinical relevance of COL6A3 in the development of CRC. In summary, the present analysis provides a basis for understanding the molecular characterization of CRC at the transcription level. COL6A3 may be a promising biomarker or target for the prognosis and treatment of CRC.