Background Anastomotic leak after esophagectomy is a major contributor to surgery-related morbidity and mortality. The purpose of this systematic review was to evaluate if positive-smoking status is associated with the incidence of this complication. Methods A systematic search of MEDLINE, EMBASE, Scopus, Web of Science and Cochrane Library was performed on April 4th, 2023. Inclusion criteria comprised human participants undergoing esophagectomy, age >= 18, n >= 5, and identification of smoking status. The primary outcome was incidence of anastomotic leak. Sub-group analysis by ex- or current smoking status was performed. Meta-analysis was performed with RevMan 5.4.1 using a Mantel-Haenszel random-effects model. Publication bias was evaluated visually with funnel plots and through the Egger test. Results A total of 220 abstracts were screened, of which 69 full-text studies were assessed for eligibility, with 13 studies selected for final inclusion. This included 16,103 patients, of which 4433 were ex- or current smokers, and 9141 were never smokers. Meta-analysis revealed an increased odds of anastomotic leak in patients with a positive-smoking status (current or ex-smokers) compared to never smokers (OR 1.44, 95% CI 1.18-1.76, I-2 = 44%, p < 0.001. Meta-analysis of six studies comparing active smokers alone to never smokers identified a significant increased odds of anastomotic leak (OR 1.80, 95% CI 1.25-2.59, p = 0.002, I2 = 0%). Meta-analysis of five studies comparing ex-smokers to never smokers identified a significant increased odds of anastomotic leak (OR 1.36, 95% CI 1.02-1.82, p = 0.04, I-2 = 0%). The odds of anastomotic leak decreased among ex-smokers compared to active smokers. Conclusion The findings of this systematic review and meta-analysis support the association between positive-smoking status and the risk of anastomotic leak after esophagectomy. Results further emphasize the importance of preoperative smoking cessation to reduce post-operative morbidity.