Introduction: In the early stages of the global COVID-19 pandemic hospital admissions for acute ischemic stroke (AIS) decreased substantially. As health systems have become more experienced in dealing with the pandemic, and as the proportion of the population vaccinated rises, it is of interest to determine whether the prevalence of AIS hospitalization and outcomes from hospitalization have returned to normal. Patients and methods: In this observational, retrospective cohort study, we compared the prevalence and outcomes of AIS during the first four waves of the pandemic to corresponding pre-pandemic periods in 2019 using administrative data collected from a nationwide network of 76 hospitals that manages 7% of all in-hospital cases in Germany. Results: We included 25,821 AIS cases in the study period (2020/2021) and used 26,295 AIS cases as controls (2019). Compared to pre-pandemic numbers, mean daily AIS admissions decreased only during wave 1 (from 39.6 to 34.1; p < 0.01) and wave 2 (from 39.9 to 38.3; p = 0.03) and returned to normal levels during waves 3 and 4. AIS case fatality increased in wave 1 only (from 6.0% to 7.6%; p = 0.03). We observed a consistent decrease in the prevalences of arterial hypertension, diabetes, and obesity among AIS cases throughout the pandemic and no changes in rates of systemic thrombolysis, mechanical thrombectomy, or decompressive craniectomy. The rate of transfer to stroke units increased only during waves 2 (by 4.6%; p < 0.01) and 3 (by 3.0%; p < 0.01). The proportion of patients with coinciding SARS-CoV-2 and AIS was low, peaking at 3.4% in wave 2 and subsequently decreasing to 0.4% in wave 4. Conclusion: In Germany, the COVID-19 pandemic seems to have had a larger effect on nationwide in-hospital AIS care during the early pandemic stages, in which AIS case numbers decreased and case fatality rose. This may reflect a nationwide “learning curve” within health care systems in providing AIS care in times of a pandemic.