Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b+ sepsis neutrophils inhibited proliferation and activation of CD4+ T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2+ immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection. The present data deposit includes processed and quality-controlled data tables for: 1. Whole blood leukocytes profiled with the BD Rhapsody platform in a cohort of 39 sepsis patients (RNA and protein count matrices, as well as their accompanying metadata table) 2. Circulating HSCs in blood profiled with the 10X multiomics platform in a cohort of 27 sepsis patients (RNA and ATAC-seq count matrices, as well as their accompanying metadata tables) IMPORTANT NOTE: The files in Version 1.0 are incomplete (missing the cell barcode list and gene/feature names).Please download Version 1.1 for the complete package (includes barcode and feature list files aligned to the matrices).