Background: The long non-coding RNA (lncRNA)) PCAT6 has been studied in many cancers, yet its relationship with colorectal cancer (CRC) remains poorly defined. Here, we conducted an analysis of The Cancer Genome Atlas (TCGA) database to better clarify the role of PCAT6 in this cancer type.Materials and Methods: Wilcoxon rank-sum tests were utilized to assess relative levels of PCAT6 in CRC tumors and normal tissues, while logistic regression analyses were utilized to compare the relationships between PCAT6 levels and clinicopathological findings. Kaplan-Meier curves and Cox regression analyses were used to gauge correlations between PCAT6 and patient survival outcomes, while the biological roles of this lncRNA were investigated via a gene set enrichment analysis (GSEA) approach.Results: PCAT6 levels were significantly correlated with CRC patient N stage (OR = 1.8 for N1&N2 vs. N0), lymphatic invasion (OR = 1.9 for Yes vs. No), M stage (OR = 2.1 for M1 vs. M0), CEA level (OR = 1.9 for >5 vs. ≤5), perineural invasion (OR = 1.9 for Yes vs. No), pathologic stage (OR = 1.9 for Stage IIIIV vs. Stage I/II), and neoplasm type (OR = 2.1 for rectal adenocarcinoma vs. colon adenocarcinoma) (all P < 0.05). CRC patients expressing higher PCAT6 levels exhibited poorer survival outcomes than those expressing low levels of this lncRNA (P = 0.017), and in univariate analyses, higher PCAT6 levels were linked to worse overall survival (OS) (HR = 1.540; 95% CI: 1.079-2.1997; P = 0.017), with this relationship also being preserved in a multivariate analysis (HR = 6.892; 95% CI: 1.713-27.727, P = 0.007). GSEA revealed high PCAT6 expression to be linked to differential DNA methylation enrichment, with high PCAT6 levels being associated with changes in base excision repair, cellular senescence, G2 M DNA damage checkpoint, chromatin-modifying enzyme, and gene silencing by RNA activity. Conclusions: PCAT6 represents a promising prognostic biomarker of poor CRC patient survival outcomes, with DNA methylation and RNA-mediated gene silencing being potentially promising mechanistic pathways whereby this lncRNA may shape patient outcomes.