Background: Chemoradiotherapy is the standard treatment for esophageal cancer, but the optimal radiation dose remains undetermined. A dose of 50.4 Gy is commonly used in both neoadjuvant and definitive settings. This study evaluates the outcomes of using 50.4 Gy in neoadjuvant chemoradiotherapy (nCRT). Methods: Patients with esophageal cancer who underwent nCRT with 50.4 Gy radiation followed by surgery between 2010 and 2023 were retrospectively analyzed. They were categorized as achieving pathological complete response (pCR patients) or not (non-pCR patients). Oncological outcomes, including overall survival (OS) and recurrence-free survival (RFS), were assessed. Results: Among 258 patients treated with nCRT, 96.5% completed the treatment protocol, and 74.4% (n=192) proceeded to surgery. These 192 patients formed the analysis cohort. The overall complication rate was 70.3%, with 19.3% classified as major complications. The 30-day and 90-day postoperative mortality rates were both 0.5%. The pCR rate was 45%. Patients with pCR had a 3-year OS rate of 72.7% and a median survival of 125 months, whereas non-pCR patients had a 3-year OS rate of 49.6% and a median survival of 35 months (p=0.002). Additionally, pCR patients had a 3-year RFS rate of 62.0% and a median RFS of 68 months, compared to 33.6% and 20 months, respectively, for non-pCR patients (p<0.001). Conclusion This study reports the outcomes of using 50.4 Gy in nCRT for locally advanced esophageal cancer. The findings affirm the efficacy of 50.4 Gy neoadjuvant chemoradiotherapy in achieving favorable long-term outcomes, particularly among patients with complete pathological response.