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ABSTRACT Sepsis has become the leading cause of death in burn patients. Furthermore, sepsis and septic complications result in significant morbidities and longer hospitalization, which has profound impacts on the healthcare system. Despite this, sepsis in burn patients is surprisingly poorly understood and characterized. This retrospective, single-institution cohort study aimed to increase our understanding of the septic response after burns. We hypothesized that different sepsis definitions will results in distinctive septic trajectories and biochemical patterns after injury. Sepsis was defined by our burn center–specific prospective definition, the American Burn Association criteria, Sepsis-3 criteria, and the Mann-Salinas criteria. Applying these definitions, we compared clinical, metabolic, and inflammatory markers in septic and nonseptic burn patients. We found that the Sepsis-3 criteria are the most reliable screening tool used before clinical diagnoses for detecting sepsis trajectories and biochemical patterns. Moreover, we characterized distinct temporal alterations in biomarkers during the pre– and post–septic periods in burn patients, which may be incorporated into future sepsis definitions to improve the accuracy of a sepsis diagnosis in burn patients.