Non-small cell lung cancer (NSCLC) is the most common cancer and cause of cancer-related mortality globally. Increasing evidence suggested that the long non-coding RNAs (lncRNAs) were involved in cancer-related death. To explore the possible prognostic lncRNA biomarkers for NSCLC patients, in the present study, we conducted a comprehensive lncRNA profiling analysis based on 1902 patients from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. In the discovery phase, we employed 682 patients from the combination of four GEO datasets (GSE30219, GSE31546, GSE33745 and GSE50081) and conducted a seven-lncRNA formula to predict overall survival (OS). Next, we validated our risk-score formula in two independent datasets, TCGA (n=994) and GSE31210 (n=226). Stratified analysis revealed that the seven-lncRNA signature was significantly associated with OS in stage I patients from both discovery and validation groups (all P<0.001). Additionally, the prognostic value of the seven-lncRNA signature was also found to be favorable in patients carrying wild-type KRAS or EGFR. Bioinformatical analysis suggested that the seven-lncRNA signature affected patients’ prognosis by influencing cell cycle-related pathways. In summary, our findings revealed a seven-lncRNA signature that predicted OS of NSCLC patients, especially in those with early tumor stage and carrying wild-type KRAS or EGFR.