Background <p>Reports regarding postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) and anastomotic leak (AL) after rectal surgery are conflicting. Distinctions between early and late AL have often been overlooked, leaving it uncertain whether the NSAID-related effects differ according to the timing of leak presentation.</p> Methods <p>This retrospective cohort study included 1663 patients undergoing minimally invasive rectal resection (2010–2021). NSAID exposure was defined as one or more dose within the first postoperative day. AL was classified as early (≤&#xa0;6 days) or late (&gt;&#xa0;6 days). Propensity score matching (PSM) and multivariable regression were used to assess associations between NSAIDs and AL. Subgroup analyses explored NSAID type/selectivity and dosing effects.</p> Results <p>The overall AL rate was 8.7% (n = 144). Early NSAID administration was associated with a higher risk of early AL in both unadjusted (7.7% vs. 4.7%,&#xa0;<i>P</i> = 0.030) and PSM-adjusted (8.4% vs. 4.6%, <i>P</i> = 0.041) analyses but not with late AL. This effect was mainly attributable to non-selective NSAIDs (odds ratio [OR] 1.717; 95% confidence interval [CI] 1.128–2.615, <i>P</i> = 0.012) and multiple NSAID doses (OR 1.687; 95% CI 1.104–2.576, <i>P</i> = 0.016). Perioperative bleeding was also more common in patients using NSAIDs (4.0% vs. 1.2%,&#xa0;<i>P</i> = 0.003). Subgroups identified a heightened NSAID-associated risk of AL in male patients (OR 1.836; 95% CI 1.190–2.832, <i>P</i> = 0.006) and patients without diverting stomas (OR 1.689; 95% CI 1.086–2.627, <i>P</i> = 0.020).</p> Conclusions <p>Early postoperative NSAIDs, particularly non-selective agents and repeated dosing, were associated with early AL after minimally invasive rectal surgery but not late AL. This study highlights the necessity of classifying AL by timing, providing a crucial new perspective for future research on NSAID effects.</p>