COPD is an inflammatory lung disease, which is often exacerbated with microbial infections resulting in worsening of respiratory symptoms. Gallic acid (GA), a naturally occurring phenolic compound is known to possess anti-oxidant/anti-inflammatory activity. We have recently reported that GA protects against the elastase (ET) induced lung inflammation and emphysema and the present work was designed to investigate the beneficial effects of Gallic acid against ET + Lipopolysachharide (LPS) induced COPD exacerbation like condition in mice model. Our data showed that i.t. administration of LPS at 21 days after ET instillation resulted in significant infiltration of inflammatory cells particularly neutrophils (p < 0.0001) into the lungs along with elevated levels of pro-inflammatory cytokines like TNF-α, IL-1β and IL-6 (p < 0.0001). Interestingly, daily administration of GA (200 mg/Kg b. wt.) starting 7 days before ET instillation, significantly blunted the ET + LPS induced inflammation as indicated by reduced number of inflammatory cells particularly neutrophils (p < 0.0001) in BALF along with suppression of myeloperoxidase activity (p = 0.0009) and production of pro-inflammatory cytokines (p < 0.0001). Further, GA also restored the redox imbalance in the lungs towards normal. Additionally, phosphorylation of p65-NF-κB was found to be reduced (p = 0.015), which was associated with downregulation in the gene expression of IL-1β (p = 0.022) and TNF-α (p = 0.04). Conversely, GA treatment resulted in increased protein levels of Nrf2 (p = 0.021) with concomitant increase in transcription of its downstream target genes HO-1 (p = 0.033) and Prdx-1 (p = 0.006). Overall, our data show that GA effectively modulates COPD exacerbation manifestations in mice potentially by restoring redox imbalance in lungs.