Background: The treatment of metastatic digestive system tumors lacks uniform biomarkers for predicting therapeutic efficacy, while circulating tumor DNA (ctDNA) offers a promising non-invasive monitoring approach. Methods and Results: This study enrolled 44 patients with metastatic digestive system tumors (esophageal, gastroduodenal, pancreatic, colorectal; stage III-IV), collecting pre-treatment tumor tissue and serial peripheral blood samples (baseline and during treatment) for next-generation sequencing (NGS) and ctDNA monitoring. Patients were categorized into ctDNA-negative (conversion to/persistent negativity, n=18) and ctDNA-positive groups (conversion to/persistent positivity, n=25) based on ctDNA dynamics. Key mutated genes included TP53 (44%), APC (15%), MUC16 (15%), OBSCN (15%), and KRAS (13%). After excluding one patient with only baseline ctDNA testing, the remaining 43 underwent ≥3 ctDNA tests (median follow-up: 12 months). The ctDNA-negative group showed superior outcomes: 1 complete response (CR), 8 partial responses (PR), 5 stable disease (SD), yielding an objective response rate (ORR) of 64.2% and disease control rate (DCR) of 100%. The ctDNA-positive group exhibited poorer outcomes: 5 PR, 5 SD, 11 progressive disease (PD), with ORR 23.8% and DCR 47.6%. Discussion: ctDNA dynamics strongly correlate with therapeutic efficacy, where ctDNA negativity predicts higher ORR/DCR and positivity indicates treatment resistance with increased progression risk. ctDNA monitoring can guide therapy selection toward more sensitive agents. Future work will expand cohorts and investigate genetic-level differences to enable earlier efficacy prediction and maximize clinical benefits.