Background: Previous research highlights central nervous system (CNS) malignancy as significant contributors to disability-adjusted life-years. However, there's a lack of information on the impact of COVID-19 infection in hospitalized CNS malignancy patients. Methods: Using the 2020 U.S. National Inpatient Sample (NIS), we investigated the impact of COVID-19 infection affected patients primarily hospitalized for CNS malignancy. We calculated adjusted odds ratios (aORs) for specific outcomes using multivariable logistic and linear regression analyses. The primary outcome was inpatient mortality, with secondary outcomes including system-based complications. Results: We identified 37,385 patients diagnosed with CNS malignancy, averaging 53.6 years old, with 57.76% being female. Among them, 0.84% (315/37,385) were also diagnosed with COVID-19. After adjusting for patient and hospital factors, COVID-19 infection was linked to higher in-hospital mortality (aOR 4.12, 95% CI: 1.55, 10.89, p = 0.004), longer stays (Beta-coefficient 6.06, 95% CI: 2.97, 9.14, p < 0.001), increased total hospital costs (Beta-coefficient 11,855, 95% CI: 1,410, 22,301, p = 0.026), elevated risks of shock (aOR 3.96, 95% CI 1.03, 15.10, p = 0.018), acute respiratory failure (aOR 4.33, 95% CI: 1.83, 10.22, p = 0.001), and sepsis (aOR 3.96, 95% CI: 1.03, 15.10, p = 0.044). Conclusions: Our study reveals that COVID-19 infection is associated with higher in-hospital mortality and multiple adverse outcomes in patients hospitalized for CNS malignancy. Further longitudinal studies are necessary to thoroughly investigate the causality of these clinical outcomes in this population.