Background <p>Aplastic anemia (AA) is a bone marrow failure syndrome characterized by impaired hematopoiesis in all cell lineages, leading to pancytopenia and hypocellular bone marrow. Although some observational studies show that viral infections may be associated with AA incidence, observational studies are insufficient to clarify the relationship between viral infection and AA because of confounding factors and reverse causality.</p> Method <p>We performed a two-sample Mendelian randomization (MR) analysis using published genome-wide association data to assess the causal relationship between AA and multiple viral infections, including COVID-19, Epstein–Barr virus, cytomegalovirus, herpes simplex virus, hepatitis B virus, human immunodeficiency virus, influenza virus, and varicella. To ensure our findings’ reliability, we eliminated linkage disequilibrium, selected strong instrumental variables, and addressed potential confounding factors before Mendelian randomization. To further validate our results and enhance their robustness, we performed sensitivity analyses and reverse Mendelian randomization.</p> Result <p>Our results suggest that COVID-19 may increase AA risk (odds ratio = 1.157, 95% confidence interval = 1.007–1.330, <i>P</i> = 0.039). However, the inverse variance-weighted of Epstein–Barr virus, cytomegalovirus, hepatitis B virus, herpes simplex virus, human immunodeficiency virus, influenza, and varicella revealed no causal relationship with AA.</p> Conclusion <p>Our results, suggesting a causal relationship between COVID-19 and AA, highlight new directions in AA etiology research.</p>