Background: Current guidelines recommend use of anticoagulation (AC) to prevent thromboembolic events for patients who develop atrial fibrillation (AF) in the setting of hypertrophic cardiomyopathy (HCM). Objective: To assess the efficacy and safety of different AC strategies for prevention of thromboembolic events, major bleeding, and mortality in patients with HCM and AF. Methods: Electronic databases of PubMed, EMBASE, Scopus, and Google Scholar were searched for relevant articles through February of 2019. Studies assessing outcomes of interest in patients with HCM and AF receiving AC versus no AC or novel oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) were selected. Risk ratios (RRs) were computed through RevMan 5.3.5 for display within forest plots. Results: This analysis identified 13 observational studies evaluating 6,082 participants. Use of AC was associated with a statistically significant reduction in thromboembolic events (RR 0.57, 95% CI 0.36-0.92; p = 0.02) compared to no AC. Furthermore, use of NOACs versus VKAs led to a statistically significant reduction in the incidence rate of combined adverse outcomes of thromboembolic events, major bleeding, and mortality (RR 0.40, 95% CI 0.19-0.85, p = 0.02). While subgroup analyses demonstrated NOACs to be statistically superior to VKAs regarding reduction in the rates of major bleeding (RR 0.67, 95% CI 0.51-0.88, p = 0.004) and mortality (RR 0.19, 95% CI 0.05-0.71, p = 0.01), there was no difference in the incidence rate of thromboembolic events (RR 0.59, 95% CI 0.28-1.25, p = 0.17) between the two AC strategies. Conclusions: This study supports existing literature suggesting AC is warranted for all patients with HCM and AF. It also demonstrates NOACs may be preferential to VKAs in this subpopulation regarding major bleeding and mortality.