Some lung cancer patients are pathologically confirmed to have lung adenocarcinoma with neuroendocrine differentiation (LUAD-ND). However, research on this subtype remains limited. This study aimed to systematically investigate the metastatic patterns and prognosis-related factors of LUAD-ND, and construct neural network-based prediction models for survival outcomes.By analyzing the Surveillance, Epidemiology, and End Results (SEER) database, we employed the Cox proportional hazards model to investigate prognostic factors for overall survival (OS) and cancer-specific survival (CSS) in patients with LUAD-ND. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) and detailed the median survival time and specific time survival probabilities for different features in the LUAD-ND population. Finally, using a neural network algorithm, we developed a predictive model for forecasting LUAD-ND's OS and CSS, evaluating its performance using the area under the receiver operating characteristic curve (AUC).Most patients with LUAD-ND were diagnosed at an advanced stage. The OS time of patients with LUAD-ND was 12 (95% CI: 10-14) months, and the CSS time was 14 (95% CI: 12-16) months. The most common distant metastatic sites were bone, followed by liver, brain, and lung. Surgery (HR =0.51; 95% CI: 0.31-0.82; P=0.006) and chemotherapy (HR =0.33; 95% CI: 0.21-0.50; P<0.001) were associated with improved OS. Similarly, surgery (HR =0.49; 95% CI: 0.28-0.84; P=0.01) and chemotherapy (HR =0.31; 95% CI: 0.19-0.49; P<0.001) were linked to better CSS. The neural network-based tool can effectively predict the prognosis of LUAD-ND, achieving an AUC of 0.852-0.864 for 6-month OS and 0.835-0.883 for 6-month CSS.Patients with LUAD-ND face a dismal prognosis, yet chemotherapy and surgical interventions can ameliorate their outcomes. The neural network tool developed in this study yields precise prognostic estimations.Copyright © 2025 AME Publishing Company. All rights reserved.