Background Previous studies have shown that the levels of serum tumor markers CEA and CA19-9 were related to chemoradiotherapy. Therefore, it has been assumed that dynamic monitoring of these markers could predict the prognosis of stage II/III rectal cancer (RC). Therefore, this study proposed to evaluate the prognostic value of changes in serum tumor biomarkers for stage II/III RC patients undergoing neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME). Methods A total of 217 patients with stage II/III RC receiving NCRT followed by TME were retrospectively analyzed. Serum CEA and CA199 levels were measured within one week before NCRT and one week before TME. The optimal cut-off points of ∆CEA% and ∆CA199% for prognosis prediction were calculated by receiver operating characteristics (ROC) analysis. Independent prognostic predictors were identified by univariate and multivariate Cox regression analyses. To avoid the efficiency of ∆CEA% and ∆CA199% on serum tumor biomarker change (STBC) score, two models including and excluding ∆CEA% and ∆CA199% were established separately in multivariate analysis. Results The optimal cut-off point for ∆CEA% and ∆CA199% were −30.29% and 20.30%, respectively. Univariate analysis showed that ∆CEA%, ∆CA199%, STBC score, ypT staging and yN staging could predict OS. ypT staging and STBC score could predict DFS. In multivariate analysis, only ∆CA199% (HR = 0.468, 95% CI: 0.220–0.994, p = 0.048), ypT staging (HR = 0.420, 95% CI: 0.182–0.970, p = 0.042), and STBC score (HR = 0.204, 95% CI: 0.078–0.532, p = 0.001) were independently related to OS; and STBC score (HR = 0.412, 95% CI: 0.216–0.785, p=0.007) and ypT staging (HR = 0.421, 95% CI: 0.224–0.792, p = 0.007) were independently related to DFS. Conclusion We established a combined STBC score to predict the prognosis of stage II/III RC patients receiving NCRT followed by TME. The predictive value of the combined score was stronger than a single marker alone and even stronger than several pathological indicators.