Background <p>Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for postoperative pain management; however, their safety in patients at risk for anastomotic leakage remains uncertain. This study evaluated the association between perioperative use of NSAIDs and anastomotic leakage after major gastrointestinal surgery.</p> Design <p>Retrospective cohort study.</p> Setting <p>Chinese People’s Liberation Army General Hospital, Beijing, China.</p> Patients <p>Individuals (<i>n</i> = 18,312) who underwent major gastrointestinal surgery between January 2008 and August 2019. Patients were divided into two groups: NSAIDs (<i>n</i> = 8405); and non-NSAIDs (<i>n</i> = 9907). Propensity score matching (PSM) was used to balance baseline characteristics between the two groups, resulting in 6458 patients per group.</p> Interventions <p>Logistic regression and subgroup analysis were employed to evaluate the association between NSAID use and postoperative outcomes, as well as the interaction with other risk factors.</p> Results <p>PSM analysis revealed that perioperative NSAIDs use was associated with a higher risk for anastomotic leakage (odds ratio 1.95, 95% confidence interval 1.48–2.57; <i>P</i> &lt; 0.001). Multivariate logistic models confirmed this association. After classifying NSAIDs into non-selective cyclooxygenase (COX) inhibitors and selective cyclooxygenase-2 (COX-2) inhibitors, multivariate logistic regression analysis demonstrated that selective COX-2 inhibitors were significantly associated with an elevated risk for leakage, whereas non-selective COX inhibitors exhibited no such association.</p> Conclusions <p>Perioperative use of selective COX-2 inhibitors, but not non-selective NSAIDs, was associated with an increased risk of anastomotic leakage after major gastrointestinal surgery. Therefore, caution should be exercised when selective COX-2 inhibitors are administered to these patients.</p>