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Abstract Background Tumours with no evidence of neuroendocrine transformation histologically but harbouring neuroendocrine features are collectively referred to as non-small cell lung cancer (NSCLC) with neuroendocrine differentiation (NED). Investigating the mechanisms underlying NED is conducive to designing appropriate treatment options for NSCLC patients. Methods In the present study, we integrated multiple lung cancer datasets to identify neuroendocrine features using a one-class logistic regression (OCLR) machine learning algorithm trained on small cell lung cancer (SCLC) cells, a pulmonary neuroendocrine cell type, based on the transcriptome of NSCLC and named the NED index (NEDI). Single-sample gene set enrichment analysis, pathway enrichment analysis, ESTIMATE algorithm analysis, and unsupervised subclass mapping (SubMap) were performed to assess the altered pathways and immune characteristics of lung cancer samples with different NEDI values. Results We developed and validated a novel one-class predictor based on the expression values of 13,279 mRNAs to quantitatively evaluate neuroendocrine features in NSCLC. We observed that a higher NEDI correlated with better prognosis in patients with LUAD. In addition, we observed that a higher NEDI was significantly associated with reduced immune cell infiltration and immune effector molecule expression. Furthermore, we found that etoposide-based chemotherapy might be more effective in the treatment of LUAD with high NEDI values. Moreover, we noted that tumours with low NEDI values had better responses to immunotherapy than those with high NEDI values. Conclusions Our findings improve the understanding of NED and provide a useful strategy for applying NEDI-based risk stratification to guide decision-making in the treatment of LUAD.