Background <p>Evidence regarding the outcomes of intravenous thrombolysis (IVT) in patients taking direct oral anticoagulants (DOACs) within 1 day before acute ischemic stroke remains limited. In this study, we aimed to evaluate the bleeding risk after IVT in patients with and without recent DOAC exposure.</p> Methods <p>This retrospective cohort study analyzed TriNetX global network data (January 2010–September 2024) in adults aged ≥ 20 years receiving IVT for acute ischemic stroke. Groups with DOAC and no anticoagulant (no-OAC) exposure within 1 day before stroke were compared. The primary outcome was intracranial hemorrhage (ICH) within 2 days after IVT. Secondary outcomes included major bleeding, blood transfusion within 2 days, and 30-day and 90-day mortality rates. Subgroup analyses examined individual DOACs (apixaban, rivaroxaban, edoxaban, and dabigatran). Propensity score matching controlled for confounders with risk differences (RDs) and odds ratios (ORs) to estimate outcome events.</p> Results <p>Among 64,667 patients (mean age 65.1 ± 16.1 years; 50.1% women), 1183 (1.8%) received DOACs, and 63,462 (98.1%) received no anticoagulants. After propensity score matching, the DOAC cohort had lower risks of ICH (RD, − 2.88% [95% CI, − 4.28% to − 1.48%]; OR, 0.36 [95% CI, 0.21–0.60]) and major bleeding (RD, − 2.54% [95% CI, − 4.53% to − 0.55%]; OR, 0.66 [95% CI, 0.47–0.91]) than the no-OAC cohort. Mortality rates were similar at 30 (OR, 0.87 [95% CI, 0.69–1.08]) and 90 (OR, 1.04 [95% CI, 0.85–1.26]) days. In subgroup analyses, apixaban showed lower ICH and mortality risks than no-OAC.</p> Conclusion <p>DOAC exposure within 1 day before stroke does not result in higher bleeding or mortality risk in patients receiving IVT for acute ischemic stroke.</p>