Esophageal cancer constitutes one of the most aggressive malignant neoplasms associated with poor clinical outcomes. While surgical resection remains the cornerstone of curative intervention, optimization of perioperative care protocols has emerged as an essential strategy to reduce postoperative complications and potentially improve long-term survival rates in patients undergoing esophagectomy. However, substantial debate persists regarding the relative importance of various perioperative risk factors and their impact on post-resection outcomes.To identify perioperative factors affecting prognosis after radical esophagectomy, aiming to improve patient outcomes through targeted interventions.A retrospective study analyzed 378 patients with esophageal cancer who underwent radical esophagectomy (McKeown, Sweet, or Ivor-Lewis procedures) from January 2022 through December 2023. All operations were performed by experienced surgeons following standardized perioperative protocols. The investigation gathered data on patient demographics, surgical parameters, tumor pathology (using the 8th edition American Joint Committee on Cancer staging system), and survival outcomes. Statistical analyses utilized Kaplan-Meier estimates and Cox proportional hazards modeling, with adjustment for confounding variables.Multivariate Cox proportional hazards analysis identified three independent predictors of survival: Tumor-node-metastasis staging [Hazard ratio (HR) = 2.31, 95% confidence interval (CI): 1.72-3.10, P < 0.001], tumor differentiation (moderate: HR = 1.46, 95%CI: 1.02-2.09, P = 0.038; poor: HR = 2.15, 95%CI: 1.47-3.14, P < 0.001), and extended postoperative analgesic use (> 5 days) (HR = 1.43, 95%CI: 1.08-1.89, P = 0.012). Kaplan-Meier analysis demonstrated significantly lower overall survival rates in patients requiring analgesics for > 5 days compared to ≤ 5 days (P = 0.003), with consistent patterns observed for both opioid (P = 0.019) and nonsteroidal anti-inflammatory drug use (P = 0.028). The extended analgesic group exhibited a higher proportion of elderly patients (48.47% vs 35.57%, P = 0.015), while other baseline characteristics and tumor features remained comparable between groups.Tumor-node-metastasis staging, tumor differentiation, and duration of postoperative analgesic use independently predict survival following radical esophagectomy, underscoring the significance of optimal pain management protocols.©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.