Therapy for leptomeningeal metastases (LM) from non-small cell lung cancer (NSCLC) is challenging, and conventional treatments have little impact on the disease course. We report three cases that were definitively diagnosed as LM from NSCLC with a mutation of epidermal growth factor receptor (EGFR) L858R. The systemic therapies of chemotherapy, local radiotherapy, and early generation tyrosine kinase inhibitors (TKIs) were implemented but ineffective. Three patients were treated with the third-generation TKI osimertinib at 80 mg daily, despite their different detection levels of T790M in the cerebrospinal fluid (CSF) and plasma, and achieved symptomatic remission, a decline of carcinoembryonic antigen (CEA) levels, and stable lesions. After the progression of LM, osimertinib at 160 mg daily further lengthened the quality of life and survival time of patients without any notable side effects during treatment. Recent related studies and our cases indicate that osimertinib has a positive effect on LM from EGFR-mutant NSCLC, regardless of T790M status.