Pulmonary pleomorphic carcinoma (PPC) is well-known for its aggressive nature that is usually resistant to platinum-based chemotherapy. On the other hand, the efficacy of an immune checkpoint inhibitor-based regimen in PPC has been elucidated. PPCs harboring epidermal growth factor receptor (EGFR) mutations are extremely rare, and the efficacy of EGFR-tyrosine kinase inhibitors in PPC is limited compared to their efficacy in EGFR-mutated adenocarcinoma. A 43-year-old female patient presenting with a lung mass with multiple brain metastases, carcinomatous pericarditis, and multiple bone metastases was referred to our department. Transbronchial biopsy confirmed the diagnosis of PPC harboring an EGFR mutation with exon 19 deletion. Subsequently, she was treated with osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, which resulted in partial response with shrinkage of the primary lesion and brain metastases. This partial response remained durable for 11 months with an ongoing regimen. The current case suggests that osimertinib would show promising effects as a first-line treatment for PPCs harboring EGFR mutations, as well as a reasonable sequence of therapy followed by immune checkpoint inhibitor-based regimens.