There is an urgent necessity to devise efficient tactics to tackle the inevitable development of resistance to osimertinib, which is a third-generation epidermal growth factor receptor (EGFR) inhibitor used in treating EGFR-mutant nonsmall cell lung cancer (NSCLC). This study demonstrates that combining itraconazole with osimertinib synergistically reduces the proliferation and migration, enhances the apoptosis of osimertinib-resistant cells, and effectively inhibits the growth of osimertinib-resistant tumors. Mechanistically, itraconazole combined with osimertinib promotes the proteasomal degradation of sonic hedgehog (SHH), resulting in inactivation of the SHH/Dual-specificity phosphatase 13B (DUSP13B)/p-STAT3 and Hedgehog pathways, suppressing Myc proto-oncogene protein (c-Myc). Additionally, DUSP13B interacts with signal transducer and activator of transcription 3 (STAT3) and modulates its phosphorylation. Interestingly, it is observed that SHH overexpression partially rescues the synergistic effects of this combination treatment strategy through the SHH/DUSP13B/p-STAT3 signaling axis. Moreover, it is found that SHH, (GLI1), p-STAT3, and DUSP13B play significant predictive roles in osimertinib resistance. In lung adenocarcinoma, p-STAT3 is positively correlated with SHH but negatively correlated with DUSP13B. Together, these results highlight the crucial role of itraconazole in reversing the acquired resistance to osimertinib and provide a scientific rationale for the therapeutic strategy of combining osimertinib with itraconazole.