Background Quercetin (Qu) belongs to a flavonoid polyphenolic compound present in fruits and vegetables which has been confirmed to exert anti-inflammatory properties. Our study aimed to explore the impacts of quercetin on lipopolysaccharide (LPS)-induced inflammatory injury and signal transduction of miR-21/DMBT1/NF-κB axis in human nasal epithelial cells (HNEpC). Methods HNEpCs were cultured and treated with 1 μg/mL of LPS and a gradient concentration (10, 100, and 200 μM) of quercetin for 24 h. Cell viability, apoptosis, and cytokines were detected to assess the inflammatory injury in LPS-exposed HNEpCs. The expressions of miR-21, DMBT1, and NF-κB mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The levels of DMBT1 and NF-κB protein were measured by western blotting. Results LPS treatment reduced cell viability, promoted cell apoptosis and inflammatory response, down-regulated miR-21 expression and up-regulated DMBT1, and NF-κB in HNEpC cells. Quercetin exerted the opposite effects to attenuate LPS-induced inflammatory injury in HNEpC cells at a concentration-dependent way. Additionally, miR-21 directly targeted DMBT1 to reduce its expression and further inducing cell viability via inhibiting cell apoptosis and inflammatory response. MiR-21 inhibition or DMBT1 over-expression weakened the protective effects of quercetin against LPS-induced inflammatory injury in HNEpC cells. Conclusions Quercetin could protect HNEpC cells against LPS-induced inflammatory injury via inducing miR-21/DMBT1/NF-κB axis. Therefore, quercetin could be utilized as a potential compound to treat for allergic rhinitis.