Presenting as atelectasis and pulmonary edema, acute lung injury (ALI) is a life-threatening condition. Inula japonica Thunb is a Chinese herbal medicine traditionally used for treating lung diseases. Nonetheless, the underlying mechanisms of the terpenoids present in the plant remain to be elucidated. In mouse models with lipopolysaccharide (LPS) induced ALI, the protective effects of total terpenoids of Inula japonica (TTIJ) were studied. ALI was developed in the mice by injecting LPS into the trachea. The underlying mechanism of TTIJ was determined using bioinformatic and RNA-seq technology. For oxidative stress and inflammation, the effects of TTIJ were verified using real-time qPCR and western blotting. In the lungs, LPS-caused histopathological changes were markedly inhibited by TTIJ. Two major pathways were identified, nuclear factor-erythroid 2-related factor 2 (Nrf2) and Toll-like receptor 4 (TLR4), primarily responsible for the TTIJ protective effects. A drastically reduced inflammation and oxidative stress in LPS-induced ALI was seen through the modulation of anti-oxidative cytokines, glutathione (GSH) and superoxide dismutase (SOD), as well as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), upon pretreatment with TTIJ. The inactivation of the MAPK/NF-κB signaling pathway reduced the phosphorylation of p65, p38, JNK, and ERK. TTIJ successfully suppressed cyclooxygenase-2 (COX-2) expression. As confirmed by the luciferase assay, several integral components of Nrf2 signaling pathways were elevated via Nrf2 receptor activation. These authors showed that TTIJ could serve as a potential therapeutic agent for ALI due to the anti-oxidant and anti-inflammatory properties Phytomedicine (2022) DOI: 10.1016/j.phymed.2022.154377.