Background: The use of anti-CD20 monoclonal antibodies, such as rituximab and ocrelizumab, has emerged as a matter of concern, in patients with coronavirus disease 2019 (COVID-19). Objective: We aimed to summarize the overall evidence on the pre-admission/pre-diagnosis use of anti-CD20 among patients with COVID-19 with regards to mortality and severe illness outcomes. Methods: A systematic literature search with no language restriction was performed in electronic databases, including PubMed, Google Scholar, Scopus, and preprint servers (medRxiv, Research Square, SSRN), to identify eligible studies published up to June 13, 2023. The outcomes of interest were the development of severe illness and all-cause mortality. A random-effects model was used to estimate the pooled odds ratio for outcomes of interest using anti-CD20 monoclonal antibodies relative to non-use of anti-CD20 monoclonal antibodies, at 95% confidence intervals. Results: Our systematic review and meta-analysis revealed significantly increased odds for development of severe illness (pooled odds ratio 2.95; 95% confidence interval 2.30, 3.78; n = 534,349) and significantly increased odds for mortality (pooled odds ratio 2.14; 95% confidence interval 1.37, 3.35; n = 333,462) with the use of anti-CD20 monoclonal antibodies, relative to non-use of anti-CD20 monoclonal antibodies, in patients with COVID-19. Conclusion: Healthcare practitioners should exercise caution when prescribing these anti-CD20 monoclonal antibodies during the COVID-19 pandemic to patients who are indicated for these agents, particularly those with underlying conditions like multiple sclerosis or rheumatoid arthritis.