Abstract: Objective To explore the effects of erlotinib on inflammation and oxidative stress in mice with septic acute lung injury (ALI) mice. Methods A total of 36 BALB/c male mice were randomly divided into three groups (n=12): a control group (Control), a sepsis model group (LPS), and an erlotinib-treated sepsis model group (ER+LPS). The ER+LPS group was intragastrically administered with 25 g/L erlotinib for 1 h, while the Control and LPS groups were intragastrically treated with the same volume of sterile normal saline for the same time. Then, the LPS group and ER+LPS group were intraperitoneally injected with 5 g/L LPS for establishing a sepsis model, while the Control group was injected with the same volume of sterile normal saline. Next, 12 hours later, the mice were sacrificed, and their lungs were collected. The injury of the lungs were detected by H-E staining. The wet/dry weight ratio (W/D) of lung tissue was detected. The arterial partial pressure of oxygen (PaO₂), arterial partial pressure of carbon dioxide (PaCO₂) and oxygenation index (PaO₂/FiO₂) were measured. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in the bronchial lavage fluid were detected by ELISA. The content of malondialdehyde (MDA), marrow peroxidase (MPO), catalase (CAT), superoxide dismutase (SOD) and reactive oxygen species (ROS) were measured by kits. The levels of phosphorylated nuclear factor (NF)-κB p65 level (p-NF-κB p65/NF-κB p65) and phosphorylated epidermal growth factor receptor (p-EGFR/EGFR), inhibitor of NF-κB (IκB), p-IκB, nuclear factor E2 related factor 2 (Nrf2) and Heme oxidase-1 (HO-1) were measured by Western blot. Results Compared with the Control group, the LPS group showed thickened lung septum, with obvious inflammatory cell infiltration, while significant increases were found as to lung injury score and W/D value in the LPS group and the ER+LPS group (P<0.05). The ER+LPS group presented remarkably relieved lung injury and decreased lung injury score and W/D value, compared with the LPS group (P<0.05). Compared with the Control group, the LPS group showed significantly increased PaCO₂ value (P<0.01), while remarkable decreases were found as to PaO₂ and PaO₂/FiO₂ values in the LPS group and the ER+LPS group (P<0.05). The ER+LPS group presented remarkably increased PaO₂ and PaO₂/FiO₂ values (P<0.01) and decreased PaCO₂ value (P<0.05), compared with the LPS group. Compared with the Control group, increased levels of p-NF-κB p65/NF-κB p65, p-EGFR/EGFR, and p-IκB protein (P<0.05) and decreased level of IκB protein (P<0.01) were found in the LPS group and the ER+LPS group, while the levels of Nrf2 and HO-1 in the LPS group were significantly reduced (P<0.01), and the levels of Nrf2 and HO-1 in the ER+LPS group increased (P<0.01). Compared with the LPS group, the ER+LPS group showed remarkable increases in the levels of IκB and Nrf2 (P<0.01), and decreases in the expression of other proteins and their phosphorylated ones (P<0.01). Conclusions Erlotinib can alleviate ALI caused by sepsis in mice, which may be related to inhibition of inflammation and oxidative stress in mice.