Propofol is a widely used intravenous anesthetic. The aim of this study was to investigate the roles of nuclear factor erythroid-2-related factor 2 (Nrf2) and NADPH oxidase (NOX) in propofol protection in inflammatory conditions induced by lipopolysaccharide (LPS). Human alveolar epithelial cells (A549 cell line) were incubated with propofol (10, 25, and 50 μmol/L) for 1 h and then treated with LPS (100 ng/mL) for 24 h. Results indicated that propofol not only attenuated LPS-induced expression of iNOS, NOX, and COX2, but decreased the production of ROS, NO, and PGE2 as well. Propofol also increased the GSH levels and the mRNA and protein levels of Nrf2. Notably, Nrf2 siRNA and the inhibitors of COX-2 and NOX attenuated the inhibition of propofol on ROS production. In conclusion, propofol reduced LPS-induced ROS production via inhibition of inflammatory factors and enhancement of Nrf2-related antioxidant defense, providing its cytoprotective evidence under inflammatory conditions.