Favorable clinical evidence suggests that the next trend in new treatments for advanced non-small cell lung cancer (NSCLC) will be combination therapies. However, inevitable epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance greatly limits the clinical efficacy of patients carrying EGFR-activating mutants. In this study, we found a patient with clinical osimertinib resistance who regained a positive response after osimertinib plus anlotinib treatment. Two osimertinib-resistant cell lines were constructed, and AXL conferred resistance to osimertinib in NSCLC cell lines. The combined effects of anlotinib and osimertinib restored sensitivity to osimertinib in two osimertinib-resistant NSCLC cell lines and in xenografts. Moreover, anlotinib inhibits the phosphorylation of AXL in both resistant cell lines. Mechanistically, we confirmed that MYC binds to the promoter of AXL to promote its transcription in NSCLC cells, and we demonstrated that anlotinib combined with osimertinib treatment enhances the anti-tumor effect by inactivating the c-MET/MYC/AXL axis to reverse osimertinib resistance in NSCLC. In conclusion, our results provide strong support that this combination therapy may be effective in enhancing the efficacy of treatments in patients with advanced NSCLC.