Shufeng Jiedu capsule (SFJDC) is a traditional Chinese medicine, which has been used for the treatment of respiratory infections for more than thirty years in Hunan (China). SFJDC protected rats against LPS-induced acute lung injury (ALI); however, the molecular mechanisms underlying the therapeutic effects of SFJDC remain unclear. Therefore, this study aimed at analyzing the major anti-inflammatory compounds of SFJDC and exploring the underlying molecular mechanisms. SFJDC dissolved in water was fingerprinted by UPLC/Q-TOF. Inflammation response was assessed by histopathological examination and ELISA assay. Arterial blood gases were also analyzed to evaluate the function of rat lungs. The expression levels of Kelch-like ECH-associating protein 1 (Keap1), Nrf2, heme oxygenase-1 (HO1), Cullin 3 (CUL3) and NQO1 were analyzed by Western blotting. Results indicated that SFJDC alleviated inflammation response by reducing the level of inflammatory cytokines, and upregulation of glutathione-S-transferase (GST) and superoxide dismutase (SOD) in lung tissues. Furthermore, SFJDC suppressed LPS-induced upregulation of Keap 1 and CUL3 in rat lungs. The expression of NRF2 HO1 and NQO1 were further upregulated by SFJDC in the presence of LPS, indicating that SFJDC might activate the NRF2-associated antioxidant pathway. In conclusion, SFJDC treatment may protect the rat lungs from LPS by alleviating the inflammation response via NRF2-associated antioxidant pathway.