BackgroundNSCLC is a malignant tumor with a high incidence. Ferroptosis presents an essential function in regulating carcinogenesis and tumor progression. However, the ferroptosis-associated prognostic model based on single-cell sequencing of NSCLC remains unexplored. Our study aims to establish a potential predictive model for NSCLC patients and provide available targeted drugs for clinical treatment.MethodsThe data on NSCLC patients were collected from TCGA and GEO databases to analyze their gene expression profiles. ConsensusCluster was adopted to divide the patients into different groups based on ferroptosis-related genes. Then, the univariable Cox and LASSO analyses were applied to data analysis and model establishment. Single-cell analysis was used to explore the risk score genes in different cell populations and states. The protein levels of these genes were also investigated through the HPA database. Drug sensitivity was evaluated in CellMiner database. CCK8 and colony formation assays were performed to validate potential drugs’ effects on lung cancer cell lines.ResultsA ferroptosis-related prognostic model involving 14 genes in NSCLC patients was established. The risk score model was developed in training set GSE31210 and validated in the test set TCGA. The low-risk score group showed a better prognosis than the high-risk score group. The single-cell analysis revealed that the risk score genes were mainly derived from lung tumor cells. Most risk score genes were more highly expressed in tumor tissue than in normal tissue, according to the HPA database. Besides, these genes were associated with 106 drugs in CellMiner database. Finally, the drug effects on NSCLC cell growth were evaluated by cck8 and colony formation.ConclusionsWe identified an effective ferroptosis-related prognostic model based on single-cell sequencing. The potential prediction model is devoted to exploring clinical therapeutic targets for NSCLC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12890-023-02445-0.