Purpose Leptomeningeal carcinomatosis (LC) is a severe complication in the advanced stage of lung adenocarcinoma, with an extremely poor prognosis. Currently, the diagnosis of LC poses challenges. Serum exosomal miRNAs (microRNAs) have been demonstrated to possess potential as viable biomarkers. However, their value in the diagnosis of LC remains unclear. Methods In this study, serum samples were collected from lung adenocarcinoma patients with LC. The control groups consisted of patients with early-stage and advanced-stage lung adenocarcinoma without LC. Serum exosomes were isolated for high - throughput RNA sequencing to screen for differential miRNAs, and the results were validated in 123 samples. Subsequently, the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic ability of exosomal miRNAs for LC. Results The results of miRNA sequencing revealed seven differentially enriched miRNAs (miRNA-1296-5p, miR-503-5p, miR-499a-5p, miR-374a-5p, miR-3173-5p, miR-370-3p and miR-885-3p). The ddPCR confirmed that the expression levels of miRNA-1296-5p, miR-499a-5p and miR-374a-5p were significantly elevated in LC, while miR-370-3p was significantly decreased (P < 0.05). ROC curve analysis showed that the AUC of the combination of miRNA-1296-5p, miR-499a-5p and miR-370-3p with CEA was 0.803 (P < 0.0001), displaying higher diagnostic power for LC. Conclusion This study suggests that the specific expression of miRNA-1296-5p, miR-499a-5p, miR-374a-5p and miR-370-3p in the serum exosomes of LC, which has diagnostic potential. And the combination of miRNA-1296-5p, miR-499a-5p and miR-370-3p with CEA can further enhance this potential.