A patient with stage Ⅳ lung adenocarcinoma harboring a missense mutation in EGFR 21 exon L858R had disease progressed after treatment with icotinib for 16 months, and then the gene test showed a T790M mutation. Then the patient was treated with the third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib, and developed abnormal behavior four months later. Six months later, the brain MRI showed the metastatic encephalomas reduced and shrunk as compared with before, but with leukoaraiosis. Later, seizures occurred during treatment in another hospital. After analysis, the occurrence of epilepsy was considered as neurotoxicity caused by osimertinib. This article first reported the rare neurotoxic side effects of osimertinib, aiming to remind the neurotoxicity of osimertinib in clinical use.