Purpose <p>Circulating tumor DNA (ctDNA) is the small fragments of DNA released by tumor cells into the blood. By detecting the abnormal changes in ctDNA in the blood, it can assist in the early screening of cancer, monitoring of treatment efficacy, early warning of recurrence, and guidance for individualized treatment. Using a systematic review and meta-analysis approach, in this study, we assessed the significant prognostic value of ctDNA in non-metastatic colorectal cancer (CRC) patients.</p> Methods <p>Studies on the predictive value of ctDNA in CRC were considered. RevMan 5.3 was used to conduct meta-analyses and subgroup investigations classified by tumor population, two-year or three-year DFS, and tumor location. The analysis included 11 trials conducted with 605 individuals. Definitions of positive ctDNA: Detection of ≥ 1 tumor-informed mutation, or tumor methylation signature above threshold, or combined mutation and fragmentome analysis.</p> Results <p>Five studies investigated the associations between pre-operative ctDNA status and patient outcomes. Patients who had higher ctDNA levels had considerably lower DFS and OS, but these differences were not statistically significant. 10 studies investigated how post-operative ctDNA status affects patient outcomes. Patients with high levels of ctDNA had worse DFS and OS, regardless of the tumor population, two-year DFS, three-year DFS, or tumor location. Surgical resection or chemotherapy increased the rate of ctDNA+/–. The study was registered on PROSPERO (CRD42024575151).</p> Conclusion <p>Post-operative ctDNA positivity is related to a poor outcome. Surgical excision or chemotherapy influences the ctDNA shift status. Circulating tumor DNA can serve as a promising prognostic indicator for patients with non-metastatic colorectal cancer. However, more studies are needed to assess the potential of ctDNA status with survival outcomes in Non-metastatic colorectal cancer.</p>