Cigarette smoke (CS) is associated with many maladies, one of which is chronic obstructive pulmonary disease (COPD). As the disease progresses, patients are more prone to develop COPD exacerbation episodes by bacterial infection, particularly to nontypeable Haemophilus influenza (NTHi) infection. The present study aimed to develop a CS-exposed mouse model that increases inflammation induced by NTHi challenge and investigate the protective effects of andrographolide, a bioactive molecule with anti-inflammatory and antioxidant properties isolated from the plant Andrographis paniculata. Female BALB/c mice exposed to 2 weeks of CS followed by a single intratracheal instillation of NTHi developed increased macrophage and neutrophil pulmonary infiltration, augmented cytokine levels, and heightened oxidative damage. Andrographolide effectively reduced lung cellular infiltrates and decreased lung levels of TNF-α, IL-1β, CXCL1/KC, 8-OHdG, matrix metalloproteinase-8 (MMP-8), and MMP-9. The protective actions of andrographolide on CS-predisposed NTHi inflammation might be attributable to increased nuclear factor erythroid-2-related factor 2 (Nrf2) activation and decreased Kelch-like ECH-associated protein 1 (Keap1) repressor function, resulting in enhanced gene expression of antioxidant enzymes including heme oxygenase-1 (HO-1), glutathione reductase (GR), glutathione peroxidase-2 (GPx-2), glutamate-cysteine ligase modifier (GCLM), and NAD(P)H quinone oxidoreductase 1 (NQO1). Taken together, these findings strongly support a therapeutic potential for andrographolide in preventing lung inflammation caused by NTHi in cigarette smokers.