Coronavirus-19, primarily a respiratory virus, also affects the nervous system. Acute ischemic stroke (AIS) is a well-known complication among COVID-19 infections, but large-scale studies evaluating AIS outcomes related to COVID-19 infection remain limited. We used the National Inpatient Sample database to compare acute ischemic stroke patients with and without COVID-19. A total of 329,240 patients were included in the study: acute ischemic stroke with COVID-19 (n = 6665, 2.0%) and acute ischemic stroke without COVID-19 (n = 322,575, 98.0%). The primary outcome was in-hospital mortality. Secondary outcomes included mechanical ventilation, vasopressor use, mechanical thrombectomy, thrombolysis, seizure, acute venous thromboembolism, acute myocardial infarction, cardiac arrest, septic shock, acute kidney injury requiring hemodialysis, length of stay, mean total hospitalization charge, and disposition. Acute ischemic stroke patients who were COVID-19-positive had significantly increased in-hospital mortality compared to acute ischemic stroke patients without COVID-19 (16.9% vs. 4.1%, aOR: 2.5 [95% CI 1.7–3.6], p < 0.001). This cohort also had significantly increased mechanical ventilation use, acute venous thromboembolism, acute myocardial infarction, cardiac arrest, septic shock, acute kidney injury, length of stay, and mean total hospitalization charge. Further research regarding vaccination and therapies will be vital in reducing worse outcomes in patients with acute ischemic stroke and COVID-19.