Overwhelming acute inflammation often leads to tissue damage during endotoxemia. In the present study, we investigated the role of Lyn, a member of the Src family tyrosine kinases, in modulating inflammatory responses in a murine model of endotoxemia. We examined lung inflammatory signaling in Lyn knockout (Lyn^-/-) mice and wild type littermates (Lyn^+/+) during endotoxemia. Our data indicate that Lyn deletion aggravates endotoxin-induced pulmonary inflammation and pro-inflammatory signaling. We found increased activation of pro-inflammatory transcription factor NF-B in the lung tissues of Lyn^-/- mice after endotoxin challenge. Furthermore, during endotoxemia, the lung tissues of Lyn^-/- mice showed increased inflammasome activation indicated by augmented caspase-1 and IL- 1β cleavage and activation. The aggravated lung inflammatory signaling in Lyn^-/- mice was associated with increased production of pro-inflammatory mediators, and elevated matrix metallopeptidase 9 and reduced VE-cadherin levels. Our results suggest that Lyn kinase modulates inhibitory signaling to suppress endotoxin-induced lung inflammation.