Background: In several settings, therapeutic-dose non–vitamin K oral anticoagulants (NOACs) are superior to aspirin for the prevention of arterial and venous thromboembolism. Purpose: To estimate differences in bleeding risks between NOACs and single antiplatelet therapy. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to June 2024 without language restrictions. Study Selection: Randomized controlled trials (RCTs) comparing therapeutic-dose NOACs versus single antiplatelet therapy, with a minimum treatment duration of 3 months. Data Extraction: Data extraction was done independently and in duplicate. Data Synthesis: Nine RCTs with 26 224 participants were included. All studies used aspirin as antiplatelet therapy. Compared with aspirin, apixaban had similar rates of major bleeding (risk difference [RD], 0.0 percentage point [95% CI, −1.3 to 2.6 percentage points]; 5 trials) and intracranial hemorrhage (RD, −0.2 percen