We report a case of epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma that transformed to Thr790Met (T790M) and mesenchymal-epithelial transition factor (MET) mutation-positive squamous cell carcinoma. A 56-year-old woman, a never-smoker, was admitted to the hospital for radical surgery of left lower lobe after 6 years, and a chest wall mass increase for 3 days. Positron emission tomography-computed tomography (PET/CT) showed soft tissue on the left side of the sternum, left 2nd, 4th, and 5th posterior ribs and left 7th rib, right 4th and 5th posterior ribs, sternal metastases; the metabolism of the tongue segment of upper left lobe are less active in the plaque. Second chest wall biopsy confirmed squamous cell carcinoma invasion or metastasis, and the Immunohistochemistry showed TTF-1 (−), CK7 (+), NapsinA (−), Ki-67 (about 30%+), CK5/6 (+), P40 (+). Genetic testing suggested that the EGFR gene 19 exon deletion mutation may be sensitive to the tyrosine kinase inhibitor (TKI); EGFR gene 20 exon T790M missense mutation may be resistant to the first-generation TKI, and sensitive to the third-generation TKI. Chemotherapy combined with osimertinib had good clinical efficacy for the treatment of T790M-positive squamous cell carcinoma. The Specific mechanism of EGFR mutation-positive lung cancer transformed into squamous cell carcinoma after treatment with the TKI has been still not completely clear, and it is necessary to accept early genetic testing, improve pathology and genetic testing several times after progress and begin to adopt the TKI adjuvant therapy as soon as possible.