Objective To investigate the effects and mechanism of Azithromycin (Azi) on lung pathological injury and oxidative stress in rats with chronic obstructive pulmonary disease (COPD). Methods Rats were randomly divided into control group, model group (COPD group) and treatment group 1(COPD+Azi(25 mg)), treatment group 2(COPD+Azi(50 mg)) and treatment group 3(COPD+Azi(100 mg)). The COPD rat model was induced by smoking combined with intratracheal instillation of lipopolysaccharide. The treatment groups were given Azi by gavage at 30 minutes before smoking. The control group and treatment groups were given the same amount of saline once a day for 4 weeks. The wet/dry weight ratio (W/D) of right lung was measured. The pathological morphology and fibrosis of lung tissue were detected by HE and MASSON staining. The protein expression of Caspase3 and MMP9 were detected by Western blot. The mRNA and protein expression of Tolllike receptor 4 (TLR4), nuclear factork B (NFkB) p65 and NF-kB inhibitor protein (IkBα) were detected by RTPCR and Western blot. The levels of tumor necrosis factorα(TNF), interleukin-1β (IL-1β), interleukin6 (IL-6), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were detected by the kit. Results Compared with model group, Azithromycin could reduce W/D ratio, pulmonary congestion, edema, inflammatory cell infiltration and collagen deposition, downregulate the protein expression of Caspase-3 and MMP-9 (P＜0.05), inhibit the content of TNFα, IL-1β and IL-6 (P＜0.05), increase SOD and GSHPx activity and decrease MDA content (P＜0.05). At the same time, Azithromycin could inhibit the phosphorylation level of TLR4, NF-kB p65 and IkBα (P＜0.05). Conclusion Azithromycin can improve the morphology and fibrosis of lung tissue and inhibit oxidative stress in COPD rats, which is related to the inhibition of activation of TLR4/NFkappa B signaling pathway.