Introduction: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Epidermal growth factor receptor (EGFR) mutations are the most common accurate gene targets. However, the lack of case reports or cohort studies on the exceptionally rare mutations limit the acquisition of deeper insights. Patient concerns: A 76-year-old female nonsmoker presented to our hospital with a one-week disease history of cough accompanied by shortness of breath. Diagnosis: Contrast-enhanced CT scan showed right pleural effusion with scattered inflammation and consolidation in the right upper lung. Tumor marker display showed obvious increased. Histopathology of the pulmonary mass combined with Immunohistochemical staining indicated lung adenocarcinoma. Contrast-enhanced magnetic resonance imaging suggested brain metastases. ECT scan showed bone metastasis. The patient was thus diagnosed as right lung adenocarcinoma of stage IV (cT3N3M1c). Next generation sequencing was performed to profile the mutation status of known oncogenic driver mutations, and only EGFR-D761Y in exon 19 (allelic frequency, AF: 0.53%) mutation was found. Interventions: The patient was accordingly treated with the third generation EGFR-Epidermal growth factor receptor tyrosine kinase inhibitor (TKI) Osimertinib (80 mg, qd). Accompanied with whole brain radiotherapy (DT3000c Gy/10f) for brain metastases, technetium methylene diphosphonate injection was performed for bone metastases. Outcomes: The efficacy of the first-line Osimertinib treatment for 1 month was assessed as PR per RECIST version 1.1. The NSCLC patient harboring EGFR-D761Y mutation detected prior to the EGFR L858R mutation was benefited from the third-generation EGFR-TKI Osimertinib and had a worse prognosis than with other EGFR mutations according to data from previous case reports. Conclusions: This case reported a NSCLC patient with de novo mutation of EGFR-D761Y responding to third generation TKI Osimertinib.