Post-operative delirium (POD) is a state of mental and neurocognitive impairment characterized by disorientation and fluctuating levels of consciousness. POD in the context of esophageal surgery may herald serious and potentially life-threatening post-operative complications, or conversely be a symptom of severe underlying pathophysiologic disturbances. The aim of the present systematic review and meta-analysis is to explore risk factors associated with the development of POD and assess its impact on post-operative outcomes. A systematic literature search of the MedLine, Web of Science, Embase and Cochrane CENTRAL databases and the clinicaltrials.gov registry was undertaken. A random-effects model was used for data synthesis with pooled outcomes expressed as Odds Ratios (OR), or standardized mean differences (WMD) with corresponding 95% Confidence Intervals. Seven studies incorporating 2449 patients (556 with POD and 1893 without POD) were identified. Patients experiencing POD were older (WMD 0.29 ± 0.13 years, P < 0.001), with higher Charlson's Comorbidity Index (CCI; WMD 0.31 ± 0.23, P = 0.007) and were significantly more likely to be smokers (OR 1.38, 95% CI 1.07-1.77, P = 0.01). Additionally, POD was associated with blood transfusions (OR 2.08, 95% CI 1.56-2.77, P < 0.001), and a significantly increased likelihood to develop anastomotic leak (OR 2.03, 95% CI 1.25-3.29, P = 0.004). Finally, POD was associated with increased mortality (OR 2.71, 95% CI 1.24-5.93, P = 0.01) and longer hospital stay (WMD 0.4 ± 0.24, P = 0.001). These findings highlight the clinical relevance and possible economic impact of POD after esophagectomy for malignant disease and emphasize the need of developing effective preventive strategies.