||Our understanding of protective vs. pathologic immune responses to Coronavirus disease 2019 (COVID-19) is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses reveal widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, with the most profound disturbances including a prominent neutrophil hyperactivation signature and monocytes with anti-inflammatory features. We further demonstrate that emergency granulopoiesis is a prominent feature of fatal COVID-19. Notably, we do not identify substantial immune perturbations in mild COVID-19 in either protein expression, RNA expression, or chromatin regulation, implying that mild disease is characterized by absent or rapidly resolved systemic immune responses. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 such as neutrophil hyperactivation that may provide targets for therapeutic intervention such as inhibiting neutrophil function through ligation of neutrophil inhibitory receptors.