Epidermal growth factor receptor (EGFR) inhibitors are the first-line target therapy of NSCLC patients with EGFR mutation. EGFR tyrosine kinase inhibitor (TKI) resistance is a major clinical challenge among non-small-cell lung cancer patients. CUB domain-containing protein 1 (CDCP1) membrane proteins are associated with poor outcomes in lung cancer patients and coordinate with EGFR TKI resistance. Targeting CDCP1 is considered a potential strategy to enhance the therapeutic effect of EGFR TKI, however, it is not available. Utilizing a high-throughput drug screening system in cell-based platforms to identify CDCP1 reducers, we identified 8PN as a CDCP1 reducer and characterized its role in lung cancer cells. Upon 8PN treatment, lung cancer cell viability, colony formation ability, migration ability, and stemness cell property were suppressed. It accumulated lung cancer cells at G0/G1 phase and increased senescent cells. In TKI-resistant lung cancer cells, the combination of 8PN and EGFR TKIs synergistically reduced cell malignancy. Notably, co-treated with 8PN and EGFR TKIs showed elevated cell apoptotic markers and decreased EGFR-downstream signaling in lung cancer cells. In a tumor xenograft mice model, 8PN combined with EGFR TKIs effectively reduced tumor growth with no severe side effects. Enhanced neutrophil-mediated cytotoxicity was found to attenuate lung cancer cell growth. Therefore, 8PN displays anti-cancer properties and enhances the anti-cancer efficacy of EGFR TKIs on lung cancer, indicating that 8PN is a promising drug accelerating the effectiveness of TKIs to treat lung cancer patients with EGFR mutation.