Background: Despite receiving curative resection, a considerable percentage of colorectal cancer (CRC) patients still experience disease recurrence. The early detection of molecular residual disease (MRD) has the potential to improve risk assessment. Methods: A total of 104 patients with stage Ⅰ-Ⅳ CRC were enrolled, of which 259 serial plasma samples were collected. Multi-gene targeted sequencing was conducted on tumor and plasma samples to identify somatic variants. Results: Among the 104 patients, 14 cases had positive landmark MRD and 32 cases had positive longitudinal MRD. Patients with positive landmark MRD had significantly higher recurrence risk compared to those with negative landmark MRD (Hazard Ratio [HR]: 7.325; 95% CI, 2.877-18.647; P < 0.001). Similarly, positive longitudinal MRD was associated with increased recurrence risk (HR: 9.385; 95% CI: 3.085-28.556; P < 0.001), with a higher HR value. Positive MRD detection preceded CT confirmed recurrence in 85.7% of patients, with a median lead time of 198.5 days. In multivariate analysis, positive-MRD was the most significant prognostic factor for DFS. The combination of KRAS variant and MRD status improved the efficiency of prognostic prediction, the area under the curve value for the combination of MRD and KRAS was higher than MRD and KRAS. By analyzing the characteristic of cfDNA fragments, we found that mutation sites tended to be enriched in shorter cell free DNA (cfDNA) fragments. Conclusions: Our study demonstrated an excellent prognostic prediction potential of circulating tumor DNA-based MRD detection among postoperative CRC patients, especially the combination of KRAS variant and MRD improved the efficiency of risk stratification through MRD. This study may facilitate the incorporation of MRD and KRAS into prognostic prediction. Our study revealed that mutation sites tended to be enriched in shorter DNA fragments, providing valuable insights for future ctDNA detection method.