Background We examined a large community‐based sample of patients with atrial fibrillation (AF) and valvular heart disease (VHD) (excluding prosthetic valves) with a goal to compare outcomes among patients with AF, with and without VHD, taking warfarin, dabigatran, and rivaroxaban. Methods and Results We identified Medicare beneficiaries enrolled in Medicare Part D benefit plan from 2011 to 2013 with newly diagnosed AF (18 137 patients with VHD [dabigatran, 1979; rivaroxaban, 2027; warfarin, 14 131] and 85 596 patients without VHD [dabigatran, 13 522; rivaroxaban, 14 257; warfarin, 57 817]). Primary outcomes of all‐cause mortality, ischemic strokes, major bleeding, and myocardial infarction were compared across the 3 anticoagulants using 3‐way propensity‐matched samples. After propensity matching, a total of 5871 patients with VHD and 40 221 patients without VHD and AF were studied. Both dabigatran and rivaroxaban were associated with significantly lower risk of death in patients with VHD with AF (dabigatran versus warfarin: hazard ratio, 0.71; 95% confidence interval, 0.52–0.98; P =0.038; rivaroxaban versus warfarin: hazard ratio, 0.68; 95% confidence interval, 0.49–0.95; P =0.022). Nongastrointestinal bleeding was significantly reduced with dabigatran and rivaroxaban versus warfarin in those with VHD (dabigatran versus warfarin: hazard ratio, 0.17; 95% confidence interval, 0.06–0.49; P =0.001; rivaroxaban versus warfarin: hazard ratio, 0.37; 95% confidence interval, 0.17–0.84; P =0.017). Ischemic stroke and gastrointestinal bleeding rates did not differ between rivaroxaban, dabigatran, and warfarin in patients with VHD. The effects of the 3 anticoagulants on outcomes were comparable in patients with and without VHD and with AF. Conclusions In this cohort of Medicare beneficiaries with VHD (excluding patients with prosthetic valves) and new‐onset AF between 2011 and 2013, novel oral non–vitamin K anticoagulants were safe and effective options for prevention of systemic thromboembolism.