Background: Little evidence is available on the long-term efficacy and safety of edoxaban, mainly due to the recent release date. The primary objective of the study was to evaluate the safety of edoxaban, defined by the incidence of major bleedings. We then aimed to evaluate the incidence of thromboembolic events and the persistence of edoxaban therapy in the long-term. Methods: In this observational cohort study, we included ischemic stroke patients enrolled in a previous study to evaluate the safety and efficacy of long-term edoxaban treatment. Data were collected by a trained investigator through a structured telephone interview. Results: Sixty-three subjects (median age 81.0 (73.5–88.0) years, 38.1% male) were included in the study, with a mean follow-up of 4.4 ± 0.7 years (range: 3.2–5.5 years). Only one patient (1.6%, 0.4%/year) presented a major extracranial bleeding, and none had cerebral hemorrhage. Six thromboembolic events occurred in five patients (7.9%): three recurrent strokes, two transient ischemic attacks, and one myocardial infarction (2.2%/year). Over a follow-up period of more than three years, 13 patients discontinued edoxaban (20.6%). Conclusions: Edoxaban seems to be effective and safe in the long-term. The persistence rate of edoxaban therapy is optimal after more than three years of treatment.