SARS-CoV-2 infection disrupts the host’s immune system, leading to altered autoimmune responses. This study investigated host autoreactivities in SARS-CoV-2 infections and their association with severe COVID-19 and the neutralizing antibody response. A magnetic bead based multiplex assay was employed to detect 20 clinically relevant circulating autoantibodies in convalescent serum samples from 38 unvaccinated, SARS-CoV-2 infected patients, 14 of whom were hospitalized. Respiratory symptoms and co-morbidities were recorded for all patients. Clustering, correlation analysis, principal component analysis and neural network modeling were used to explore the relationship between autoantibodies, hospitalization and SARS-CoV-2 neutralization. The presence of one autoantibody correlated with the detection of multiple others. Although anti-IFNα antibodies were detected in 11% of the cohort and strongly associated with elevated levels of anti-ENAs, there was no significant association with clinical outcome. COVID-19 hospitalization was significantly associated with the collective expression of autoantibodies targeting three extractable-nuclear antigens (ENAs): SSA/Ro52, Jo-1 and RNP. In contrast, a separate set of autoantibodies targeting three ENAs: RNP/Sm, PCNA and Scl-70 along with the aminoacyl t-RNA synthetase PL-12, was strongly associated with the antiviral humoral immune response. In summary, this study has identified self-antigens targeted in hospitalized COVID-19 patients. Furthermore, we establish a novel link between the host autoantibody response and the humoral immune response, which plays a crucial role in neutralizing SARS-CoV-2 variants.