High‐grade neuroendocrine tumors (NETs) of the lung consist of small‐cell lung cancer (SCLC) and large‐cell neuroendocrine carcinoma (LCNEC). Both exhibit aggressive malignancy with poor prognosis. The transformation of lung adenocarcinoma (ADC) to SCLC or LCNEC also contributes to acquired resistance to epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs). Despite initially being responsive to chemotherapy, high‐grade NET patients inevitably develop drug resistance; thus, novel therapeutic targets are urgently needed for these patients. Our study reported that VGF (nerve growth factor inducible), a factor mainly expressed in neurons during neural development, is highly expressed in SCLC and LCNEC as well as in a subset of ADCs, whereas targeting VGF attenuates cancer cell growth and tumor formation. High VGF expression was associated with advanced stage SCLC and predicted poor prognosis in lung ADC. In addition, EGFR‐TKI selection enriched VGF expression in TKI‐resistant ADC under epigenetic control. The VGF locus possessed the HDAC1 binding site, and treatment of ADC cells with the HDAC1 inhibitor induced VGF expression. High VGF expression was associated with chemoresistance, and silencing VGF induced BMF and BCL2L11 expression and rendered lung cancer cells sensitive to chemotherapy drugs. These findings suggested the potential of VGF as a prognostic factor and therapeutic target in lung cancers with neuroendocrine feature. What's new? Neuronal survival factor VGF is highly expressed in neuroendocrine tissues. However, its biological and clinical significance in lung neuroendocrine tumors is elusive. Our study shows that high VGF expression in neuroendocrine tumors prevents cancer cell apoptosis. VGF is regulated by HDAC1‐mediated epigenetic control in lung adenocarcinoma, and silencing VGF decreases tumor growth through enhanced cancer cell apoptosis. High VGF expression leads to resistance to chemotherapy drugs, including epidermal growth factor receptor‐tyrosine kinase inhibitors, and predicts poor survival in lung cancer patients. The findings indicate the potential of VGF as a theranostic factor in lung cancer.