Background: The best anticoagulation choice for patients undergoing transcatheter aortic valve replacement (TAVR) with indications of oral anticoagulation (OAC) remains uncertain. We carried out a comprehensive analysis adopting updated evidence that investigated the efficacy and safety of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) in this population. Methods: A systematic search has been conducted through PubMed, Embase, and Cochrane Library to collect randomized controlled trials (RCTs) and real-world studies comparing the therapy outcomes of DOACs with VKAs in patients undergoing TAVR with indications of OAC up to Dec 2021. Included studies reported all-cause mortality, bleeding, stroke, or composite endpoint. A random-effects model was used and followed a sensitivity analysis based on the heterogeneity. In addition, five scenario analyses were performed to robust our findings. Results: Our analysis included 11 articles enrolling a total of 8934 patients undergone TAVR with indications of OAC (DOACs group = 3890, VKAs group = 5044). Pooled analysis revealed no significant different risk of all-cause mortality (aHR: 0.95, 95% CI: 0.65–1.39, I{}^{\mathrm{2}}: 90.6%), stroke (aHR: 0.86, 95% CI: 0.55–1.35, I{}^{\mathrm{2}}: 44.3%), bleeding (aHR: 0.83, 95% CI: 0.61–1.13, I{}^{\mathrm{2}}: 76.3%), and composite endpoint (aHR: 1.05, 95% CI: 0.88–1.24, I{}^{\mathrm{2}}: 11.7%) in the DOACs and VKAs groups. Various forms of death, stroke and bleeding, including cardiovascular death (aHR: 0.92, 95% CI: 0.64–1.33, I{}^{\mathrm{2}}: 34.1%), hemorrhagic stroke (aHR: 0.63, 95% CI: 0.23–1.75, I{}^{\mathrm{2}}: 22.7%), ischemic stroke (aHR: 0.79, 95% CI: 0.56–1.15, I{}^{\mathrm{2}}: 0.0%), transient ischemic attack (aHR: 0.75, 95% CI: 0.40–1.41, I{}^{\mathrm{2}}: 0.0%), major or life-threatening bleeding (aHR: 0.96, 95% CI: 0.74–1.24, I{}^{\mathrm{2}}: 27.9%), and minor bleeding (aHR: 0.90, 95% CI: 0.52–1.57, I{}^{\mathrm{2}}: 54.3%), also showed similar rates among DOACs and VKAs groups. The results based on five scenarios confirmed the said findings. Conclusions: Compared with VKAs, the efficacy and safety of DOACs were comparable for treating TAVR patients combined with anticoagulation indications. Further large-scale RCTs investigating more detailed scenarios are still needed to confirm the optimal anticoagulation strategy.