(1) Background: Acute ischemic stroke (AIS) is a possible complication of the coronavirus disease 2019 (COVID-19). Safety and efficacy data on reperfusion therapies (RT)—intravenous thrombolysis and endovascular treatment (EVT)—in stroke patients with COVID-19 is lacking. (2) Methods: We performed a retrospective nationwide multi-center pair-matched analysis of COVID-19 patients with AIS who underwent RT. We included adult COVID-19 patients with AIS who were treated with RT between 16 March 2020 and 30 June 2021. All subjects were paired with non-infected controls, matched for age, sex, stroke arterial vascular territory, and RT modality. The primary outcome measure was a favorable functional outcome defined by the modified Rankin scale (mRS 0–2). (3) Results: Thirty-one subjects and thirty-one matched controls were included. The median baseline National Institutes of Health Stroke Scale (NIHSS) score was higher in the COVID-19 group (16 vs. 12, p = 0.028). Rates of ischemic changes and symptomatic intracerebral hemorrhages did not differ significantly between the two groups at 24 h after RT. The median NIHSS 24 h after reperfusion remained significantly higher in the COVID-19 group (16 vs. 5, p = 0.003). MRS 0–2 at discharge was significantly less common in COVID-19 patients (22.6% vs. 51.8%, p = 0.018). Three-month mortality was 54.8% in the COVID-19 group versus 12.9% in controls (p = 0.001). (4) Conclusion: Reperfusion therapies on AIS in COVID-19 patients appear to be safe; however, functional outcomes are significantly worse, and 3-month mortality is higher.