Abstract The COVID-19 pandemic has caused a global public health crisis of unprecedented proportions. SARS-CoV-2, the etiological agent of COVID-19, primarily infects the respiratory tract, leading to a range of symptoms including dry cough, fever, and shortness of breath. While many cases remain mild or asymptomatic, a subset progress to acute respiratory distress syndrome (ARDS) requiring ICU admission and ventilation support. Rapid progress has been made to understand the pathogenesis and immune response to SARS-CoV-2 infection; however, there remain a number of unanswered questions. Recent evidence has indicated that mild cases of COVID-19 are controlled by an effective innate immune response. However, in moderate and severe cases, the immune response to infection appears to be dysfunctional leading to low levels of interferon and high inflammatory responses. Here, we examined a cohort of patients admitted to the Emory University Hospital with severe COVID-19. Patients had variable neutralization titers measured by FRNT assay, which did not correlate age or disease severity. Flow cytometry immune subset analysis, cytokine and chemokine quantification, and single cell RNA sequencing (scRNAseq) revealed an inflammatory phenotype including a significant shift in the myeloid compartment compared to healthy donors. Numbers of pDCs and non-classical (CD14−CD16+) monocytes in the blood were decreased, while intermediate monocytes (CD14+CD16+) cells were increased. Additionally, stimulated CD14+ cells from healthy donors were able to limit SARS-CoV-2 infection in a human airway epithelial culture system. This suggests a role for monocytes to combat infection by SARS-CoV-2 that may be dysregulated in severe patients.