New direct oral anticoagulants are recommended for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). However, no data are available regarding the optimal time to start oral anticoagulation after acute stroke. The aim of our study was to evaluate the occurrence of symptomatic bleedings within 90 days from acute cardioembolic stroke in patients who received early treatment with Edoxaban. The study was conducted according to an observational prospective uncontrolled design. Secondary endpoints were the incidence of major bleeding (MB), hemorrhagic transformation within the first week of Edoxaban treatment, minor bleeding, and recurrent stroke. We included patients with Alberta Stroke Program Early Computed Tomography Score (ASPECTS) ≥ 6, NVAF, no previous treatment with any other anticoagulant, preserved swallowing function. Patients with estimated Glomerular Filtration Rate < 50 mL/min, body weight < 60 kg, receiving cyclosporine, dronedarone, erythromycin, ketoconazole, or previous treatment with any other anticoagulant were excluded. We enrolled 75 elderly patients with moderate disability. We did not observe any symptomatic intracranial bleeding or recurrent stroke after 3 months of treatment with early administration of Edoxaban, while two gastrointestinal MB, and 11 minor bleedings were reported. Asymptomatic bleeding was evaluated with a brain Magnetic Resonance Imaging performed 5 days after starting anticoagulant treatment with Edoxaban. Specifically, we observed small petechiae in 12% of the patients, confluent petechiae in 6.6% of the patients, and small hematoma of the infarcted area in 2.7% of the patients. No intralesional hematoma or hemorrhagic lesion outside the infarcted area were observed. According to our data, the early use of Edoxaban seems to be safe in patients after cardioembolic stroke. However, due to the small size of the study sample, and the short follow-up period, further studies are needed.