Oxidative injury can occur in the lung through the generation of reactive oxygen species (ROS) via redox cycling owing to intentional or accidental ingestion of paraquat (PQ), a common herbicide. A wide array of phytochemicals has been shown to reduce cellular oxidative damage by modulating cytoprotective genes. Quercetin, a well-known flavonoid, has been reported to display cytoprotective effects by up-regulating certain cytoprotective genes. In this context, we investigated the effect of quercetin on PQ-induced cytotoxicity in alveolar A549 cells, modulation of antioxidant genes, activation of transcription factor-Nrf2 and its target HO-1 expression. Quercetin reduced PQ-induced cytotoxicity in A549 cells that was evaluated by both 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Modulation of antioxidant genes was compared when cells were treated with PQ, quercetin and both using qRT-PCR. Activation of transcription factor-Nrf2 and induction of its target gene, HO-1 was demonstrated by western blot analysis. A remarkable reduction in the ROS level as well as an increase in the total cellular glutathione (GSH) level occurred when PQ-exposed cells were treated with quercetin. Our findings suggest that quercetin may be used to mitigate or minimize oxidative stress via reducing the generation of ROS. Copyright © 2012 John Wiley & Sons, Ltd.