Although sepsis in burn patients is a major contributor to mortality, treatments are not always effective and underlying mechanisms have yet to be completely elucidated. NLRP3 inflammasome orchestrates burn‐induced, inflammatory‐driven pathophysiologic processes. Here, we determined the mechanism of NLRP3 inflammasome activation on bacterial clearance and mortality in burn sepsis. We obtained tissue and blood from 30 wild‐type and 30
Nlrp3−/− mice. Mice were subjected to a two‐hit model of 25–30% TBSA scald burn followed by Pseudomonas aeruginosawound infection 72 hours after injury. We also obtained tissue from 34 adult burn patients (≥18 years of age) with early (0–11 days post‐burn) and later (≥12 days post‐burn) surgical time‐points and ten healthy controls. Murine studies indicated that Nlrp3−/− had 30% improved survival and bacterial clearance at the site of injury and is systemically relative to burn sepsis wild type. Greater macrophage and neutrophil infiltration occurred acutely after infection (12 hours) to the site of injury and adipose tissue. This was followed by increased macrophage and neutrophil infiltration to lymphoid organs and liver beyond the acute phase (24 and 72 hours). Interestingly, Nlrp3ablation increased acute systemic inflammation (IL‐6, TNF‐α, IL‐1β). Septic burn patients had persistently increased adipose NLRP3 by‐product expression beyond the acute phase that was more pronounced in late‐onset sepsis. Our findings suggest that Nlrp3genetic ablation enhanced acute tissue‐specific inflammatory responsiveness. Likely, this occurs by paradoxically increasing acute immune infiltration and inflammation with a non‐persistent response. Clinically, persistent NLRP3‐mediated inflammation occurs in septic versus normal burn patients and potentially detrimentally impacts patient outcomes.