Mouse models of sepsis typically involve systemic administration of bacteria or toxins that may not reflect the kinetics of the transition from a local infection to invasive systemic disease. In this study we have established a model of S. pyogenes skin infection that initially involves bacterial growth at the local site of infection followed by dissemination to distant organs. Invasion to the bloodstream was associated with escalating cytokine release, an initial rapid leukocytosis and thrombocytosis that progressed to leukopenia and thrombocytopenia over time. Importantly, organ dysfunction occurred and was characterized as increased plasma biomarkers, histopathological changes in organ biopsies and proteome reorganization in the affected organs. Platelet activation preceded thrombocytopenia and organ damage, therefore the organotypic platelet proteome was also investigated. Quantitative proteomics and immunofluorescence microscopy determined that platelets mobilized to the local site of skin infection but also accumulated in the liver and kidney at the same time as bacteria disseminated to these organs. S. pyogenes was shown to bind to platelets ex-vivo and platelet activation occurred. We conclude that bacteria-mediated platelet activation may contribute to the pathogenesis of streptococcal sepsis which progresses from thrombocytosis to platelet activation and finally thrombocytopenia. Platelet aggregates accumulate in organs and may contribute to the organ dysfunction observed. Further studies are required to determine the effects of antiplatelet therapy at distinct phases of this sepsis progression.