Obstructive sleep apnea (OSA) has been considered as one of the risk factors for ischemic stroke, but the impact of OSA on wake-up stroke (WUS) is not well studied. We aimed to determine the relationship between OSA and WUS. We prospectively recruited 71 patients with mild to moderate ischemic stroke during hospitalization. Patients were classified into WUS and non-WUS. A full-night sleep respiratory study was performed between 3 and 14 days after stroke onset. Demographic data, sleep respiratory data, heart rate variability, stroke risk factors, stroke classification and sleep-related scales were recorded. We compared the differences in the variables between the two groups and determined the independent variables associated with WUS. Of the 71 patients, 26 (36.6%) had WUS. The patients with WUS had a significantly higher apnea-hypopnea index (23.1 ± 19.4 vs. 12.5 ± 11.9, p = 0.016), obstructive apnea index (7.8 ± 9.7 vs. 3.0 ± 4.0, p = 0.021) and lower mean blood oxygen saturation (95.1 ± 1.5 vs. 95.8 ± 1.3, p = 0.046) than the non-WUS patients. There were no significant differences in demographic data, stroke risk factors, sleep-related scales or heart rate variability. Logistic regression revealed that severe sleep-disordered breathing (apnea-hypopnea index ≥30) was the only independent variable associated with WUS (OR 6.065, 95% CI 1.451-25.350; p = 0.014). We conclude that in patients with mild to moderate ischemic stroke, OSA is the only risk factor associated with WUS, which cannot be distinguished clinically from non-WUS.