Leptomeningeal metastasis (LM) is one of the most serious complications of advanced non-small cell lung cancer (NSCLC) and lacks standard treatment. Patients with LM often have a poor prognosis. Here, we report a 51-year-old man diagnosed as advanced lung adenocarcinoma and gene sequencing indicated no sensitive driver gene mutation. Pemetrexed and cisplatin plus bevacizumab was administered as first-line therapy. He received pembrolizumab plus nab-paclitaxel as second-line therapy and developed neurological symptoms soon. Later, he was diagnosed LM by cerebrospinal fluid (CSF) cytology and gene sequencing of lung tissue rebiopsy demonstrated epidermal growth factor receptor (EGFR) sensitive mutation. The patient received high-dose (160mg) osimertinib therapy but still could not tolerate severe neurological symptoms and developed cardiac adverse event. After that, standard-dose (80mg) osimertinib plus anlotinib was administered and this treatment regimen resulted in the alleviation of neurological symptoms. As the recent follow up, the curative effect was evaluated stable disease (SD) and the patient gained a progression-free survival (PFS) of more than 15 months. We report this successful salvage therapy of osimertinib plus anlotinib in an advanced lung adenocarcinoma patient who developed LM after failure on previous treatment until EGFR mutation was confirmed through rebiopsy.