Abstract The factors that control the development of an effective immune response to the recently emerged SARS-CoV-2 virus are poorly understood. In this study, we provide a cross-sectional analysis of the dynamics of B cell responses to SARS-CoV-2 infection in hospitalized COVID-19 patients. We observe changes in B cell subsets consistent with a robust humoral immune response, including significant expansion of plasmablasts and activated receptor-binding domain (RBD)–specific memory B cell populations. We observe elevated titers of Abs to SARS-CoV-2 RBD, full-length Spike, and nucleoprotein over the course of infection, with higher levels of RBD-specific IgG correlating with increased serum neutralization. Depletion of RBD-specific Abs from serum removed a major portion of neutralizing activity in most individuals. Some donors did retain significant residual neutralization activity, suggesting a potential Ab subset targeting non-RBD epitopes. Taken together, these findings are instructive for future vaccine design and mAb strategies.