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R4667 --> The Gulf War Illness (GWI) is a multiple, unexplained health concern that persists even after 30 years of the first Persian Gulf War (1990‐91). Veterans' prolonged, low systemic inflammation level is linked with war theater chemical exposure, including nerve gas drug pyridostigmine‐bromide (PB) and pesticides (permethrin). However, the clear etiology and underlying mechanism of chronic liver inflammation in GWI are poorly understood. Using the established mouse model of GWI, we report a crucial mechanism of extracellular high‐mobility group box protein1 (HMGB1) mediated M1 polarization in the inflamed GWI liver. We observed an increased HMGB1 and CD63 (extracellular vesicle marker), HMGB1‐CD68 (active Kupffer cells), and TLR4‐Flottilin‐2 colocalization events in GW chemical treated mice suggests that extracellular HMGB1 activates TLR4 signaling in Kupffer cells. The treated mice liver showed increased proinflammatory cytokines and M1 polarization markers MCP1, IL1β, IL6, IL12, and IL23. The treated mice also showed increased MyD88 and P65 expression, suggesting the activation of TLR4 signaling pathway and associated inflammatory response in GWI. Interestingly, the mice co‐exposed with GW chemicals and Nexinhib 20 (neutrophil exocytosis inhibitor 20; extracellular vesicle maturation inhibitor) showed a significant decrease in observed extracellular HMGB1, TLR4 signaling pathway, and proinflammatory cytokines. Thus, Nexinhib 20 ameliorates liver inflammation and improves liver pathology of the GWI mice. These results suggest that GW chemical leads to extracellular HMGB1‐TLR4 mediated chronic liver inflammation, abrogated by Nexinhib 20. In summary, the study clearly indicates that extracellular packaging and exocytosis of HMGB1 play a crucial role in GWI associated liver inflammation, and inhibiting this mechanism by Nexinhib 20 improves liver inflammation in a mouse model of GWI. [ABSTRACT FROM AUTHOR]