Quercetin, a member of the flavonoids, has been heralded as chemopreventive agent, generally because of its free radical-scavenging and antiproliferative activities. In this process, NF-E2-related factor-2 (Nrf2) plays a role in protecting cells from oxidative damage; however, the exact mechanisms in which bronchial epithelial cells respond to quercetin by activating Nrf2 are not fully understood. Here, we report the role of extracellular signal-regulated kinase (ERK) activation in response to quercetin. Quercetin treatment decreased the viability of human bronchial epithelial BEAS-2B cells in a dose- and time-dependent manner. ERK1/2 was activated within 10 min of quercetin addition and then remained increased above control level throughout 48 h, whereas AKT phosphorylation was suppressed from the first 1 h of quercetin treatment. Inhibition of Erk1/2 phosphorylation attenuated quercetin-induced loss of cell viability. Nrf2 levels in both nuclear and whole cell lysates increased after quercetin treatment and was accompanied by the increase of heme oxygenase-1 (HO-1) protein level, indicating that increased HO-1 expression is Nrf2-mediated. Activation of the Nrf2/HO-1 system after quercetin treatment was suppressed by the pretreatment with MEK inhibitor, PD98059. Also, silencing Nrf2 with siRNA decreased cell viability and augmented cytotoxic effect of anticancer drug LBH589. Overall, our results indicate that quercetin induces the up-regulation of Nrf2-mediated HO-1 expression, at least in part, via MEK/ERK1/2 signaling, as an adaptive mechanism which may provide advantages for cell proliferation and enhance survival despite endogenous and/or exogenous oxidative insults.