The poor performance of single-gene lists for prognostic predictions in independent cohorts has limited their clinical use. Here, we employed a pathway-based approach using embedded biological features to identify reproducible prognostic markers as an alternative. We used pathway activity score, sure independence screening, and K-means clustering analyses to identify and cluster colorectal cancer patients into two distinct subgroups, G2 (aggressive) and G1 (moderate). The differences between these two groups with respect to survival, somatic mutation, pathway activity, and tumor-infiltration by immunocytes were compared. These comparisons revealed that the survival rates in the G2 subgroup were significantly reduced compared to that in the G1 subgroup; further, the mutational burden rates in several oncogenes, including , , and , were significantly higher in the G2 subgroup than in the G1 subgroup. The enhanced activity of the critical pathways such as MYC and epithelial-mesenchymal transition may also lead to the progression of colorectal cancer. Taken together, we established a novel prognostic classification system that offers meritorious insights into the hallmarks of colorectal cancer.