Rationale: Burn-induced acute lung injury (ALI) is a common clinical disorder associated with high mortality even in the absence of inhalational injury. Identification of endogenous triggers that mediate the early onset of remote ALI after burn represents an important goal but remains poorly defined. Objectives: We investigated the role of pro-inflammatory neuropeptide, substance P (SP), in instigating remote ALI and its effects on respiratory function early after severe local burn injury. Methods: A 30% total body surface area full-thickness burn was induced in wild-type (WT) mice, preprotachykinin-A PPT-A gene deficient mice, which encodes for SP, and PPT-A^-/- mice challenged with exogenous SP, followed by ALI and lung function analysis. Measurements and Main Results: Endogenous SP production was heightened in burn-injured WT mice, which induced significant elevation of pro-inflammatory cytokines, chemokines, and endothelial adhesion molecules; concurrent with disruption of pulmonary permeability barrier, excessive neutrophil infiltration and severe ALI. Additionally, decreased neutral endopeptidase and elevated matrix metalloproteinase-9 were evident. Notably, disruption of respiratory function demonstrates a critical role of SP in lungs after burn. These effects were significantly attenuated in PPT-A^-/- mice; while exogenous administration of SP to PPT-A^-/- mice restored the inflammatory response and ALI. Furthermore, analysis of neurokinin-1-receptor (NK1R), which SP binds preferentially to, revealed that SP in-conjunction with burn injury regulates NK1R expression. Conclusions: We show evidence that the absence of a single endogenous factor, SP, significantly provides early protection against burn-induced ALI in mice with marked improvement in respiratory function. Thereby, blockade of SP maybe beneficial in preventing early inflammation and ALI in critically burn-injured patients.