Antithrombotic therapy plays a crucial role in secondary prevention following ischemic stroke from the acute phase. Numerous trials, along with a meta-analysis, contributed to establishing aspirin as the primary medication for secondary stroke prevention. According to the Cochrane Database of Systematic Review 2022, initiating antiplatelet therapy with aspirin at a dose of 160 mg to 300 mg daily within 48 hours of stroke onset reduces the risk of death or dependency at the end of follow-up. Other antiplatelet drugs, such as clopidogrel, cilostazol, prasugrel, and intravenous ozagrel sodium, are also available within the Japanese Health Care Insurance System. Two pivotal trials from the 2010s underscored the effectiveness and safety of dual antiplatelet therapy (DAPT) using aspirin and clopidogrel, administered for 21 days to 3 months following acute ischemic stroke or transient ischemic attack. However, the extension of DAPT with aspirin and clopidogrel beyond 3 months may result in substantial bleeding risks. Although prasugrel offers a rapid, potent, and consistent inhibition of platelet aggregation and can be used in place of clopidogrel, there is a lack of substantial real-world clinical data on its use in acute ischemic stroke. It is important to recognize that antiplatelet drugs might not be beneficial and could even increase the risk of hemorrhagic events in cardioembolic stroke. In cases of ischemic stroke with nonvalvular atrial fibrillation, direct oral anticoagulants are the primary choice if applicable. Warfarin continues to be the anticoagulant of choice for secondary stroke prevention in patients with mechanical valve replacements. In patients who have undergone intravenous thrombolysis, antithrombotic therapy is generally delayed for up to 24 hours, although there are no definitive guidelines for the period during and immediately after mechanical thrombectomy. This review provides an overview of the current status of antithrombotic therapy for acute ischemic stroke.