Background: While neoadjuvant therapy followed by esophagectomy is the standard of care for locally advanced esophageal cancer, the role of adjuvant therapy is uncertain. As such, this review aims to analyze esophageal cancer patients who previously underwent neoadjuvant therapy followed by a curative resection (negative margins) to determine whether additional adjuvant therapy is associated with improved survival outcomes. Methods: MEDLINE, EMBASE, and CENTRAL databases were searched up to August 2020 for studies comparing patients with esophageal cancer who underwent neoadjuvant therapy and curative resection with and without adjuvant therapy. Primary outcome was overall survival (OS), and secondary outcomes were disease-free survival (DFS), locoregional recurrence, and distant recurrence at 1 and 5-years. Random effects meta-analysis was conducted where appropriate. Grading of recommendations, assessment, development, and evaluation (GRADE) was used to assess the certainty of evidence. Results: Ten studies involving 6,462 patients were included. 6,162 (95.36%) patients from 7 studies received adjuvant chemotherapy, whereas 296 (4.58%) patients from 3 studies underwent either adjuvant radiotherapy or chemoradiotherapy. When compared to patients who received neoadjuvant therapy and esophagectomy alone, adjuvant therapy groups experienced a significant overall survival benefit by 48% at 1-year (RR 0.52, 95%CI 0.41-0.65, P < 0.001, moderate certainty). This reduction in mortality was consistent at long-term 5-year follow-up (RR 0.91, 95%CI 0.87-0.96, P < 0.001, moderate certainty). Subgroup analysis on pathologic node positive patients demonstrated a consistent survival benefit at 1-year (RR 0.57, 95% CI 0.42-0.77, P < 0.001, moderate certainty) and 5-year (RR 0.89 95%CI 0.84-0.95, P < 0.001, moderate certainty). While adjuvant therapy presented no benefit for the T0-2 stage subgroup, patients with T3-4 disease experienced a significant reduction in mortality with the addition of adjuvant therapy at both 1-year (RR 0.51, 95% CI 0.41-0.63, P < 0.001, moderate certainty), and 5-years (RR 0.91, 95% CI 0.85-0.97, P = 0.005, moderate certainty). Due to incomplete reporting, the added benefit of adjuvant therapy was uncertain regarding DFS, locoregional recurrence, and distant recurrence. Conclusions: Adjuvant therapy after neoadjuvant treatment and curative esophagectomy provides improved OS at 1 and 5 years, but the benefit for DFS and locoregional/distant recurrence was uncertain due to limited reporting of these outcomes.