Background <p>The aim of this study was to evaluate the prognostic value of tumor regression grade (TRG) in patients with esophageal cancer after neoadjuvant therapy and to validate the prognostic value of a novel TRG system (nTRG) system including the number of metastatic lymph node stations (S system) in patients with esophageal cancer after neoadjuvant therapy.</p> Method <p>A total of 514 patients were enrolled in the study cohort, and survival differences between categories of the TRG or S system were tested using the Kaplan–Meier (KM) method and log-rank, with the former graded according to College of American Pathologists criteria. The nTRG system was developed by combining the two systems. We compared the discrimination, accuracy, and clinical value of the current American Joint Committee on Cancer (AJCC) post-neoadjuvant staging system (ypTNM) with the&#xa0;nTRG, which integrates TRG and novel metastatic lymph node station number.</p> Results <p>In the training cohort, the discrimination, accuracy, and clinical value of nTRG staging groups were better than those of the ypTNM staging groups, which is reflected in the higher C-index and decision curve analysis values. Results were similar in the validation cohort. Multivariate analysis showed that nTRG stage (<i>P</i> &lt; 0.001), smoking (<i>P</i> = 0.02), and recurrence (<i>P</i> &lt; 0.001) were independent prognostic factors.</p> Conclusion <p>The nTRG staging system demonstrates superior predictive efficacy to the AJCC ypTNM staging system.</p>