Guidelines do not support the combination of direct oral anticoagulants (DOACs) and the antiepileptic drug levetiracetam, due to potential relevant P-glycoprotein (P-gp) mediated interaction that might result in decreased DOACs concentrations and increased thromboembolic risk. However, there is no systematic data on the safety of this combination. The aim of this study was to find patients concurrently treated with levetiracetam and DOAC, assess their plasma concentrations of DOAC, and the incidence of thromboembolic events. From our registry of patients on anticoagulation drugs we identified 21 patients concomitantly treated with levetiracetam and DOAC, 19 patients with atrial fibrillation and two patients with venous thromboembolism. Eight patients received dabigatran, 9 apixaban and 4 rivaroxaban. For each subject blood samples were collected for determination of trough DOAC and trough levetiracetam concentrations. The average age was 75 ± 9 years, 84% were males, HAS-BLED score was 1.8 ± 0.8, and in patients with atrial fibrillation CHA2DS2-VASc score was 4.6 ± 2.0. The average trough concentration level of levetiracetam was 31.0 ± 34.5 mg/L. Median trough concentrations of DOACs were for dabigatran 72 (range 25–386) ng/mL, for rivaroxaban 47 (range 19–75) ng/mL, and for apixaban 139 (range 36–302) ng/mL. During the observation period of 1388 ± 994 days none of the patients suffered a thromboembolic event. Our results did not demonstrate a reduction in DOACs plasma levels during levetiracetam treatment, suggesting that levetiracetam could not be an important P-gp inducer in humans. DOAC in combination with levetiracetam remained effective therapy to protect against thromboembolic events.