This study provides a comprehensive multi-omics analysis of the human host response during acute leptospirosis. We performed integrated transcriptomic and proteomic profiling of peripheral blood mononuclear cells (PBMCs) from clinically confirmed leptospirosis patients and healthy controls. Our analysis reveals widespread dysregulation of host pathways, including potent activation of TNF-alpha/NF-kappaB signaling, interferon responses, and inflammatory and immunometabolic pathways. We identified a conserved core host response signature, validated key immune mediators in an ex vivo whole-blood infection model, and pinpointed a multi-protein signature associated with the disease. This dataset offers a valuable resource for understanding the molecular mechanisms of host-pathogen interactions in leptospirosis and identifies potential biomarkers and therapeutic targets.