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Chemotherapy plays crucial roles in the clinical treatment of non-small cell lung cancer (NSCLC). Nevertheless, acquired chemoresistance is a common and critical problem that limits the clinical application of chemotherapy. Quercetin (QUE), a natural bioflavonoid, has significant antitumor potential, which has been verified in many drug-resistant cancer cell lines and animal models. Here, we explored whether QUE could reverse the resistance of NSCLC to paclitaxel (PTX)-based therapy. The results of cell viability revealed that QUE could synergistically enhance the cytotoxicity of PTX in A549 and A549/Taxol cells. Furthermore, Akt and ERK phosphorylation had no significant changes in A549/Taxol cells treated with PTX. However, it was significantly inhibited by the combination treatment of QUE and PTX. To improve the antitumor activity of PTX due to its hydrophobicity and eliminate its toxicity, we prepared targeted biodegradable cetuximab chitosan nanoparticles (Cet-CTS NPs) to deliver PTX and QUE using ionic cross-linking technique. The targeted NPs displayed a particle size of 290 nm and sustained release of PTX and QUE. In addition, the targeted Cet-CTS NPs loaded with PTX and QUE inhibited tumor growth in PTX-resistant A549/Taxol cells. Cet-QUE NPs decreased tumor growth in PTX-resistant xenografts. In conclusion, the administration of QUE by using Cet-CTS NPs could provide a prospective strategy for the treatment of PTX-resistant lung cancer. Schematic illustration of Cet-QUE/PTX NPs preparation and its sequential release process for therapy. In the experiment, we prepared the Cetuximab modified chitosan nanoparticle (Cet-CTS NPs) loaded with Quercetin (QUE) or Paclitaxel (PTX) using ionic cross-linking technique. The synergic effect and reversal influence of co-administration of Cet-CTS NPs with QUE or PTX were evaluated in vitro and in vivo, we found that co-administration of Cet-CTS NPs with QUE and PTX displayed higher killing effect on drug-resistant lung cancer cells via inhibiting the phosphorylation of Akt and ERK. Unlabelled Image • Cet-PTX NPs/Cet-QUE NPs were produced using chitosan bonded Cet for promoting active targeting. • NPs had excellent physicochemical properties which were low size distributions and PDI with positive zeta potential. • Cet-QUE/PTX NPs could synergistically fight against NSCLC and enhance the chemotherapeutic effect of PTX-based therapy. • Cet-QUE NPs could reverse the chemoresistance in PTX-based therapy by inhibiting the phosphorylation of Akt and ERK. [ABSTRACT FROM AUTHOR]