Objective: To conduct an exploratory analysis of individualized treatment of leptomeningeal metastasis (LM) in patients with non-small cell lung cancer (NSCLC). Methods: Eighteen NSCLC patients with LM admitted to Fujian Provincial Cancer Hospital from December 2018 to March 2020 were selected. Clinical and treatment data and survival follow-up of patients with LM were collected. Results: Fourteen patients harbored epidermal growth factor receptor (EGFR) mutations, 1 anaplastic lymphoma kinase (ALK) fusion, 1 proto-oncogene 1 (ROS1) fusion, and 2 wild-type. LM patients with genetic mutations received tyrosine kinase inhibitor (TKI)-based targeted therapy with or without combined systemic and local comprehensive treatment. A total of 14 patients received intrathecal chemotherapy (ITC) with pemetrexed. According to the response assessment in neuro-oncology (RANO), 12 of 18 patients were evaluated as responding, 2 were stable, and 4 were progressive. Conclusion: Individualized comprehensive treatment can prolong the survival of patients of LM. The targeted therapy of patients harbored genetic mutations is still the cornerstone, and ITC of pemetrexed may become a treatment option.