Purpose <p>Non-vitamin K antagonist oral anticoagulants (DOACs) are the preferred treatment over vitamin K antagonists (VKAs) for patients with atrial fibrillation (AF). However, AF patients at risk or with history of falls seldom receive anticoagulants due to the bleeding risk. The objective was to assess the efficacy and safety of DOACs in AF patients with history or risk of falls.</p> Methods <p>A systematic literature review was conducted until October 31, 2024. Primary outcomes were stroke/systemic embolism (SSE) and major bleeding (MB). Bayesian network meta-analyses were conducted. Hazard ratios (HRs) with 95% credible intervals (CrI) quantified the effect of drugs; cumulative ranking curves (SUCRA) were used to determine their hierarchy.</p> Results <p>Out of 961 articles, 10 articles (5 randomized controlled trials and 5 observational studies) were retained for quantitative synthesis. Risk of bias was moderate to serious. In reducing the risk of SSE compared with VKAs, apixaban had a SUCRA of 0.87 (HR 0.72, 95% CrI 0.59–0.96), followed by rivaroxaban (HR 0.80; 95% CrI 0.63–0.99; SUCRA 0.68), edoxaban (HR 0.96; 95% CrI 0.48–1.91; SUCRA 0.38) and dabigatran (HR 0.92; 95% CrI 0.68–1.28; SUCRA 0.37). In reducing the risk of MB, compared with VKAs, edoxaban had a SUCRA of 0.86 (HR 0.66; 95% CrI 0.50–0.92) followed by apixaban (HR 0.67; 95% CrI 0.55–0.87; SUCRA 0.83), and dabigatran (HR 0.79; 95% CrI 0.64–1.00; SUCRA 0.54).</p> Conclusions <p>DOACs appear to have different efficacy and safety profiles and overall are preferable over VKAs in patients with AF with a history or risk of falls. Because of bias, further research is warranted.</p> Trial Registration <p>PROSPERO identifier no. CRD42020201086.</p>