Colorectal cancer (CRC) remains a significant health concern in the world. The existing standard of care guidelines for CRC surveillance falls short of effectively and timely detecting recurrence or metastasis. In recent years, circulating tumor DNA (ctDNA) has emerged as a promising material for minimal residual disease (MRD) detection. In this paper, we provide an exhaustive review of the methods utilized for MRD detection via ctDNA, present evidence supporting the potential of ctDNA MRD as a valuable biomarker in clinical applications, and engage in a discussion regarding ongoing ctDNA MRD based clinical trials in CRC. Lastly, we offer insights into future prospects of ctDNA-based MRD methodological advancements and clinical research. It’s foreseeable that more sensitive, flexible, and economic MRD detection methods will emerge with the deeper research on cfDNA genomics, fragmentomics, methylomes, and nucleosome imprinting. At the same time, MRD-guided intervention study will evolve for revolutionizing the treatment paradigm of CRC.