This study aims to investigate the effect of Fritillariae Cirrhosae Bulbus extract on inflammation and oxidative stress in chronic obstructive pulmonary disease rats. Forty SD rats were randomly divided into blank control group, model group and drug administration group. The COPD rat model was established by lipopolysaccharide (LPS) combined with cigarette smoking (CS) exposure. The drug administration group was intragastrically administrated Fritillariae Cirrhosae Bulbus extract, control group and model group were given the same amount of distilled water, once a day for six weeks. Subsequently, inflammatory cells in peripheral blood and bronchoalveolar lavage fluid (BALF) were detected. The pathological changes of lung tissue were observed by HE staining. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), IL-1β and heme oxygenase 1 (HO-1) in BALF were determined by ELISA. Malonydialdehyde (MDA) content and glutathione/oxidized glutathione (GSH/GSSG) ratio in lung tissues were detected. The expression levels of phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK), phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated c-Jun N-terminal kinase (p-JNK) and nuclear factor erythroid 2-related factor 2 (NRF2) in lung tissues were detected by immunohistochemistry. Results showed that compared with the model group, Fritillariae Cirrhosae Bulbus extract could improve the symptoms of body weight loss, cough, wheezing and fatigue caused by LPS and CS exposure, and inhibited the increased count of white blood cell in peripheral blood and BALF. Moreover, it alleviated inflammatory cell infiltration, inhibited pulmonary interstitial increase and lung tissue parenchymatization, ameliorated annular changes of small bronchial, and mitigated lung tissues injury in a dose-dependent manner. Meanwhile, the levels of IL-6, TNF-α and IL-1β in BALF were significantly decreased in medium and high dose groups. The level of HO-1 in BALF was significantly increased in high dose group. MDA content was significantly decreased and GSH/GSSG ratio was significantly increased in medium and high dose groups. Furthermore, the expression of p-ERK and p-JNK in lung tissue was significantly decreased in dose-dependent manner in Fritillariae Cirrhosae Bulbus extract groups, and NRF2 expression was significantly increased in high-dose group. In conclusion, Fritillariae Cirrhosae Bulbus extract has a good therapeutic effect on COPD, and its mechanism may be related to inhibiting the expression of p-ERK and p-JNK in MAPK signaling pathway and activating NRF2 signaling pathway, thus alleviating inflammation and oxidative stress.