Circulating tumor DNA (ctDNA) is a promising biomarker for predicting minimal residual disease (MRD) and guiding treatment decisions in patients with colorectal cancer (CRC). This study aimed to examine the study designs and settings of ongoing clinical trials that use ctDNA to guide treatment decisions and to determine the best timing for detecting MRD in non-metastatic CRC. We searched PubMed, Embase, Web of Science, Cochrane Library, and clinicaltrials.gov for English language records. The ctDNA settings from the clinical trials were categorized by randomization to ctDNA testing, treatment options based on ctDNA results, and the timing of ctDNA testing relative to adjuvant therapy. For prospective studies, a network meta-analysis using a frequentist approach was conducted to examine the pairwise associations between different ctDNA timing strategies and MRD, defined as recurrence, relapse, and progression. The main approaches in ctDNA-based interventional trial designs were categorized as ctDNA-guided treatment, ctDNA-by-treatment, ctDNA-guided surveillance, and ctDNA-enriched adjuvant therapy for guiding treatment decisions, including both escalation and de-escalation strategies, and surveillance. Overall, both preoperative and postoperative ctDNA detection were linked to higher risks of progression, with pooled hazard ratios (95% confidence intervals) of 5.23 (2.10-13.00) and 7.95 (5.30-11.91), respectively. Among the timing strategies, ctDNA testing after adjuvant therapy was the most effective for identifying high-risk patients, strongly suggesting the presence of residual disease. This study comprehensively reviewed the clinical settings of ctDNA testing in ongoing trials and provided evidence supporting the selection of post-adjuvant therapy as the optimal timing for ctDNA testing.