A maladaptive inflammatory response has been implicated in the pathogenesis of severe COVID-19. This study aimed to characterize the temporal dynamics of this response and investigate whether severe disease is associated with distinct gene expression patterns. We performed microarray analysis of serial whole blood RNA samples from 17 patients with severe COVID-19, 15 patients with moderate disease and 11 healthy controls. All study subjects were unvaccinated. We assessed whole blood gene expression patterns by differential gene expression analysis, gene set enrichment, two clustering methods and estimated relative leukocyte abundance using CIBERSORT. Neutrophils, platelets, cytokine signaling, and the coagulation system were activated in COVID-19, and this broad immune activation was more pronounced in severe vs. moderate disease. We observed two different trajectories of neutrophil-associated genes, indicating the emergence of a more immature neutrophil phenotype over time. Interferon-associated genes were strongly enriched in early COVID-19 before falling markedly, with modest severity-associated differences in trajectory. In conclusion, COVID-19 necessitating hospitalization is associated with a broad inflammatory response, which is more pronounced in severe disease. Our data suggest a progressively more immature circulating neutrophil phenotype over time. Interferon signaling is enriched in COVID-19 but does not seem to drive severe disease.