Background: Circulating tumor DNA (ctDNA) is considered an effective indicator for real-time monitoring of therapeutic efficacy and prognosis prediction in various malignant tumors. We conducted a study to investigate whether serial ctDNA monitoring can predict recurrence, disease progression, and prognosis in pancreatic cancer. Methods: A total of 231 with pancreatic cancer were prospectively enrolled. Among them, 167 patients (52 in the resection group, 115 in the palliative treatment group) were assessable for serial ctDNA at scheduled intervals (total ctDNA evaluations: 614). CtDNAs were analyzed using individualized droplet digital PCR to measure the mutant allele fraction of KRAS G12/13 screening multiplex Kit, with the results reported as variant allele fraction (VAF). The percent changes of ctDNA (Δ ctDNA) were correlated with radiologic response at each evaluation. Associations between ctDNA and recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) were evaluated. Results: CtDNAs were detected in 143 of 167 eligible patients (85.6%). The detection rate increased with the advancing stage (P= 0.016) and varied based on the metastatic site (liver: 98.0% vs. peritoneum, 88.9%; P= 0.011). In the resection group, there was no significant difference in Δ ctDNA regarding recurrence, nor were there statistically significant difference in terms of RFS and OS based on postoperative ctDNA detection. Conversely, in the palliative treatment group, patients with progressive disease (PD) exhibited significantly higher Δ ctDNA compared to those with stable disease (SD) or partial response (PR) (P< 0.001). Patients whose Δ ctDNA increased before radiologically PD had their Δ ctDNA levels increased an average of 2.53 months earlier. Notably, higher ctDNA were linked to shorter PFS (HR 1.84; 95% CI 1.07 to 3.18, P = 0.03) and OS (HR 2.15; 95% CI 1.20 to 3.86, P = 0.01) in metastatic patients. Patients who achieved ctDNA clearance at 8 weeks demonstrated more favorable outcomes in terms of PFS (HR 0.53; 95% CI 0.30 to 0.92, P = 0.02) and OS (HR 0.50; 95% CI 0.28 to 0.90, P = 0.02). Similar benefits were observed for those who experienced at least one ctDNA clearance (PFS, HR 0.27; 95% CI 0.16 to 0.44, P < 0.001; OS, HR 0.31; 95% CI 0.19 to 0.50, P< 0.001). Conclusions: Our findings suggest that serial ctDNA monitoring holds promise in predicting treatment response and prognosis for unresectable pancreatic cancer patients.