Survival post-burn injury has improved over the past few decades. However, there are still a large proportion of patients that do not survive. Survival can be affected by the complexity of the burn injury itself, pre-existing medical conditions, and complications. The purpose of this study was to characterize the phases of inflammatory and metabolic trajectories in survivors and non-survivors. Furthermore, we compared the trajectories for early and late death in non-survivors. We conducted a cohort study in patients (aged ≥ 18 years) with a burn injury admitted to our provincial burn centre. Blood samples, clinical indicators, and metabolic markers were selected based on time post-injury as follows: 0–1, 2–4, 5–10, 11–18, 19–28, ≥ 29 days. The inflammatory profile included IL-1β, interferon-γ, IL-1 receptor antagonist, IL-6, IL-10, IL-8, TNF-α, GM-CSF, and MCP-1. Hypermetabolism was assessed by resting energy expenditure. Clinical outcomes included organ biomarkers, morbidities, and hospital length of stay. Groups were compared using Student’s t-test, Mann-Whitney U, Fisher’s exact, and χ2 test as appropriate; P value of <0.05 considered statistically significant. Multivariable regression was used to model the association between survivors and non-survivors, adjusting for patient and injury characteristics. We studied 1,749 patients, mean age 47 ± 18 years and 33 ± 13% TBSA burn, with 1,623 survivors and 126 non-survivors. Demographics and injury characteristics were significantly different among survivors and non-survivors: mean age was 45 ± 18 versus 62 ± 18 (p<0.0001), proportion of inhalation injury 206 (13%) versus 73 (58%) (p<0.0001), and 11 ± 12% versus 48 ± 30% TBSA burn (p<0.0001) respectively. Of the non-survivors, 73 (58%) of died within the first four days of injury. After adjustment for patient and injury characteristics, organ biomarkers including creatinine, BUN, ALP, ALT, AST, bilirubin, lactate, and pH; and cytokines IL-6, IL-8, IL-10, MCP-1, TNF-α, G-CSF, and MCP-1 were significantly higher in non-survivors (p<0.05). Notably, these differences were further augmented among early and late non-survivors. Survivors and non-survivors express distinct inflammatory and metabolic responses post-injury. Identifying the relationship of concomitant immune activation and suppression among survivors and non-survivors may improve patient outcomes by defining and altering inflammatory trajectories. Elucidating the differences in trajectories among early and late non-survivors could better allow for prediction and identification of patients at risk to die.