Sepsis accounts for significant global mortality, morbidity and economic burden. Whilst the new Sepsis-3 definition has augmented patient identification, supportive care and survival, a lack of clinically-relevant animal models has limited our understanding of sepsis disease dynamics over time. Specifically, there are key knowledge gaps in chronic pathology underpinning increased mortality rates of sepsis survivors, leading to inadequate development of effective therapeutics. To address this shortcoming, we have established multiple preclinical mouse models of sepsis using clinical bacteria isolates and incorporating the standard care of broad-spectrum antibiotics and fluid resuscitation. We demonstrate that resuscitated septic mice overcome the initial bacterial insult, display various biological, functional and histological signs of multi-organ damage, and exhibit altered immunological homeostasis upon recovery. We further observe that differences in pathogen species and/or route of infection impact disease kinetics and severity. Given the greater incidence of sepsis in elderly populations, we are utilising aged mice in our models to investigate the therapeutic efficacy of sodium ascorbate treatment as part of the MRFF-funded MEGASCORES study. Additionally, we are leveraging our models to characterise dynamic metabolomic and proteomic changes throughout the sepsis disease course and recovery to identify putative therapeutic targets. Together, clinically-relevant murine sepsis models will improve our understanding of sepsis pathogenesis beyond the initial hyperinflammatory phase and provide an invaluable platform to test novel therapeutics to limit organ damage and restore homeostasis.