Background <p>Left atrial appendage closure (LAAC) has become the treatment of choice for stroke prevention in patients with nonvalvular atrial fibrillation who are at high risk of bleeding or with contraindications for anticoagulation. However, the optimal duration of anticoagulation after LAAC remains uncertain. The aim of this study was to evaluate the optimal duration of treatment with novel oral anticoagulants (NOACs) after LAAC.</p> Method <p>We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for studies related to LAAC published from inception to 20 December 2023, and performed a meta-analysis comparing the efficacy and safety of 45-day and 3-month postoperative NOAC treatment using R4.3.1 software.</p> Results <p>A total of 14 studies were included in this study, of which 4 were prospective cohort studies and 10 were retrospective cohort studies. The incidence of stroke or transient ischaemic attack (0.018 [95% CI: 0.007–0.033] in the 3-month group and 0.005 [95% CI: 0.001–0.011] in the 45-day group; <i>P</i> = 0.07) and the incidence of device-related thrombus (0.025 [95% CI: 0.002–0.065] in the 3-month group and 0.020 [ 95% CI: 0.007–0.037] in the 45-day group; <i>P</i> = 0.81) were not significantly different. However, the incidence of major bleeding was significantly greater in the 3-month group than in the 45-day group (0.033 [95% CI: 0.018–0.053] in the 3-month group and 0.003 [95% CI: 0.000–0.008] in the 45-day group; <i>P</i> &lt; 0.01).</p> Conclusions <p>Compared with the 3-month scheme, 45&#xa0;days of postoperative anticoagulation significantly reduced the risk of major bleeding in patients without compromising the efficacy of preventing stroke or transient ischaemic attack and device-related thrombus.</p> Trial registration <p>Our meta-analysis was registered in the PROSPERO international database (CRD42024524661).</p>