Background: In patients with lung adenocarcinoma and leptomeningeal metastases, it remains unknown whether non-classical mutations in the epidermal growth factor receptor (EGFR) gene can be detected in the cerebrospinal fluid (CSF) and how it may be used to design directed therapy. Methods: On April 18, 2018, the Interventional Department of Tianjin Huanhu Hospital admitted a 34-years-old male patient with lung adenocarcinoma and leptomeningeal metastasis. An emergency lateral ventriculoperitoneal shunt was performed to relieve the clinical symptoms of intracranial hypertension. Next-generation sequencing (NGS) of the CFS specimens revealed a mutation in EGFR exon 18 p.G719A, and afatinib was administered. Follow-up showed significantly relieved headache, with significantly reduced soft leptomeningeal abnormal enhancement as revealed by enhanced magnetic resonance imaging and significantly smaller tumors in the left lung by chest computed tomography. Carcinoembryonic antigens (CEAs) in cerebrospinal fluid and peripheral blood were significantly reduced. The patient responded well to afatinib, with mild adverse complications. The patient died on October 27, 2019 from respiratory failure as a result of lung infection unrelated to cancer progression. The overall survival (OS) using afatinib was 530 days. Conclusion: CSF can be used as a liquid biopsy for NGS gene detection in patients with lung adenocarcinoma and leptomeningeal metastases. Afatinib exhibits a beneficial effect in patients with lung adenocarcinoma and leptomeningeal metastases harboring the EGFR exon 18 p.G719A mutation.