Quercetin is a potent cancer therapeutic agent and dietary antioxidant present in fruit and vegetables. Quercetin prevents tumor proliferation by inducing cell cycle arrest and is a well known cancer therapeutic agent and autophagy mediator. We investigated whether quercetin enhances TRAIL-induced tumor cell death and the possible mechanism in human lung cancer cells. We identified that quercetin markedly enhanced TRAIL-mediated lung cancer cell death. Quercetin treatment dose-dependently decreased the p62 protein expression and increased GFP-LC3B. Autophagy flux inhibitor, chloroquine treatment blocked the enhancing effects of TRAIL-induced apoptosis by quercetin. Our results indicated that quercetin enhanced TRAIL-induced cell death via autophagy flux activation, and also suggest that quercetin may be a therapeutic agent against human lung cancer via combination therapy with many anticancer drugs including TRAIL.