BACKGROUND: Locally advanced rectal cancer (LARC) typically involves neoadjuvant chemoradiotherapy (nCRT) followed by surgery (total mesorectal excision, TME). While achieving a complete pathological response (pCR) is a strong indicator of a positive prognosis, the specific benefits of adjuvant chemotherapy after pCR remain unclear. To address this knowledge gap, we conducted a systematic review and meta-analysis to assess the potential advantages of adjuvant therapy in patients who achieve pCR. METHODS: In this study, we searched Medline, Embase, and Web of Science databases for relevant research. We focused on binary outcomes, analyzing them using odds ratios (ORs) with 95% confidence intervals (CIs). To account for potential variability between studies, all endpoints were analyzed with DerSimonian and Laird random-effects models. We assessed heterogeneity using the I statistic and employed the R statistical software (version 4.2.3) for all analyses. RESULTS: Thirty-four studies, comprising 31,558 patients, were included. The outcomes demonstrated a significant difference favoring the AC group in terms of overall survival (OS) (HR 0.75; 95% CI 0.60-0.94; p = 0.015; I = 0%), and OS in 5 years (OR 1.65; 95% CI 1.21-2.24; p = 0.001; I = 39%). There was no significant difference between the groups for disease-free survival (DFS) (HR 0.94; 95% CI 0.76-1.17; p = 0.61; I = 17%), DFS in 5 years (OR 1.19; 95% CI 0.82-1.74; p = 0.36; I = 43%), recurrence-free survival (RFS) (HR 1.10; 95% CI 0.87-1.40; p = 0.39; I = 0%), and relapse-free survival (OR 1.08; 95% CI 0.78-1.51; p = 0.62; I = 0%). CONCLUSION: This systematic review and meta-analysis found a significant difference in favor of the ACT group in terms of survival after pCR. Therefore, the administration of this treatment as adjuvant therapy should be encouraged in clinical practice.