To evaluate clinical literature for direct oral anticoagulants (DOACs) therapy for non-Food and Drug Administration approved indications. Articles from MEDLINE, Cochrane Library, Google Scholar, and OVID databases were reviewed from 1946 through September 4, 2020. Fully published studies assessing DOACs for atrial fibrillation (AF) with valvular heart disease (VHD), heart failure (HF), left ventricular thrombus (LVT), superficial vein thrombosis (SVT), or pulmonary hypertension (PH) were evaluated. Our review showed that DOACs are safe to use in patients with AF and VHD except for mitral stenosis or mechanical heart valve. Rivaroxaban 2.5 mg twice daily should be used with caution in patients with HF with reduced ejection fraction until further evaluation is performed. Four retrospective studies for DOAC use in patients with LVT showed conflicting results. One phase 3 randomized controlled trial showed noninferiority of rivaroxaban to fondaparinux for SVT treatment. The use of DOACs for pulmonary arterial hypertension was not evaluated in any clinical study, but 2 retrospective studies for the use of DOACs in patients with chronic thromboembolic PH (CTEPH) showed similar efficacy between DOACs and warfarin. This review provides clinicians with a comprehensive literature review surrounding DOAC use in common off-label indications. DOACs can be considered for AF complicated by VHD except for mitral stenosis or mechanical valve replacement. DOACs (especially rivaroxaban) are considered as an alternative therapy for SVT and CTEPH. Further prospective studies for DOAC uses are needed for HF or LVT.