Background: Many countries worldwide reported side effects of the coronavirus disease 2019 (COVID-19) pandemic that have influenced the care of patients with other diseases in both acute and elective settings. Patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) represent the major patient population suffering from an autoimmune inflammatory demyelinating disease of the central nervous system. We aimed to analyze MS and NMOSD hospitalizations, the application of plasmapheresis therapy, and the dynamic during different periods of the COVID-19 pandemic in Germany. Methods: We conducted a nationwide retrospective cross-sectional study using the administrative database of all hospitalized patients with the main diagnosis of MS and NMOSD, including the information on the application of plasmapheresis therapy. We included full-year data from 1463 hospitals of all MS and NMOSD patients hospitalized in 2019 and 2020 in Germany (n = 87,453). We compared case numbers and plasmapheresis therapy rates of the different pandemic periods in 2020 with the corresponding periods in 2019. Results: We observed a substantial decline of MS and NMOSD patients' hospitalizations during the different pandemic periods, with the most remarkable decline during the first wave of the pandemic (First diagnosis of MS: -16.8%; relapsing-remitting MS: -34.0%; secondary progressive MS: -48.9%; primary progressive MS: -43.8%; NMOSD: -19.2%). Treatment rates with plasmapheresis increased for MS and NMOSD patients in 2020 compared to 2019 (1.8% versus 1.6%, p = 0.003; 14.0% versus 9.3%, p < 0.001), with a substantial increase during the first wave of the pandemic, especially in NMOSD patients (19.7% versus 8.4%, p < 0.001). Conclusion: There was a marked decline of MS and NMOSD patients' hospitalizations during the different pandemic periods in 2020, with the most substantial reduction during the pandemic's first wave and in progressive MS patients. MS and NMOSD patients who needed rescue relapse treatment continued to receive plasmapheresis therapy in Germany.