Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in men and women globally. Investigating genetic ground differences between normal and CRC tissues would be significant for identifying some key oncogenic pathways and developing anti-cancer agents. Methods: Weighted gene co-expression network analysis (WGCNA) method was used to screen out core pathways related to the clinical traits of CRC patients. Then, multiple databases were utilized to further verify the hub genes obtained from data mining. Finally, to explore the role of hub genes in CRC, cell counting and EdU assays were performed. Results: The results of the WGCNA analysis showed that a module (turquoise module) was highly related with CRC differentiation grade (R =0.53, P<0.0001). Enrichment analysis indicated that genes of the turquoise module were remarkably enriched in multiple inflammatory processes and pathways. Among all hub genes of the turquoise module, the m RNA levels of YIAT1 and CCL5 were significantly higher in CRC than in normal colon tissues. SPIT1 expression was highly positively correlated with the level of CCL5. The results of the cell counting, EdU, CCK-8, and CFSE staining assays showed that interfering with STAT1 and CCL5 could inhibit the proliferation of CRC cells. Conclusions: Our study indicated that the STAT1-CCL5 axis is an important modulator in the development of CRC through promoting cell proliferation. Moreover, the levels of STAT1 and CCL5 might be valuable biomarkers for CRC screening.