The pathogenesis of human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform ’omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that Ebola virus infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity. Display omitted •Multi-omics analysis of peripheral blood from Ebola disease (EVD) patients was performed•Pancreatic enzymes may contribute to host-mediated tissue damage in fatal EVD•Neutrophils may dysregulate adaptive immunity and cause tissue damage in fatal EVD•A redundant panel of diverse biomarkers can predict EVD outcomes Eisfeld et al. comprehensively evaluated changes in host molecules in plasma and peripheral immune cells of Ebola virus disease (EVD) patients. Their results suggest new mechanisms of EVD pathogenesis and putative biomarkers for predicting EVD outcomes. Moreover, datasets associated with this work are an important community resource for further research.