Tyrosine kinase inhibitors (TKIs) have greatly improved the survival of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-TKI sensitive mutations such as L858R and exon 19 deletions. The third-generation EGFR-TKI osimertinib, an irreversible TKI, is approved as a therapy for advanced NSCLC with EGFR sensitive mutations. Recently, osimertinib showed antitumor activity against NSCLC in patients harboring an uncommon mutation such as an exon 20 insertion. Herein, we present a patient diagnosed with stage IV NSCLC with an EGFR L858R/V843I mutation complex who benefited remarkably from osimertinib therapy. The patient was a 41-year-old Chinese female who complained of backache in October 2018. Computed tomography (CT) and magnetic resonance imaging (MRI) scans showed a mass in the right lung and brain metastasis. A whole-body bone scan revealed bone metastases. Targeted next-generation sequencing (NGS) of hydrothorax was performed and the coexistence of somatic L858RI and V843I mutations in EGFR exon 21 was discovered on November 13, 2018. Osimertinib therapy (80 mg daily) was administered for 12 months which resulted in an initial partial response (PR). At that point, the right lower lung lesion enlarged, indicating disease progression. Thus, the patient began combination therapy with osimertinib (80 mg daily) and bevacizumab (500 mg daily), leading to disease stabilisation until June 2020. Of note, during treatment, the patient achieved sustained control of metastatic brain and bone lesions. To the best of our knowledge, we report here the first known case of an NSCLC patient with a somatic EGFR L858R/V843I mutation complex who responded well to osimertinib. Our findings provide theoretical guidance and expand the list of potential beneficiaries of EGFR-TKI therapy.