EML4-ALK rearrangement is common in lung adenocarcinoma. The ALK inhibitors remarkably inhibit lung adenocarcinoma and reveal long-term beneficial effects in several patients. Advanced genetic testing technology reveals that EML4-ALK rearrangement has been observed in patients with lung squamous cell carcinoma. In the present study, we report a case of a 53-year-old patient with EML4-ALK rearranged in lung squamous carcinoma; PET/CT scan revealed brain and multiple bone metastases. First-line ALK-TKI combined with local stereotactic body radiation therapy indicated progression-free survival of 9 months. After progressive disease, treatment was switched to lorlatinib, with little efficacy and a total overall survival of 11 months. The emergence of drug resistance revealed that the genetic test result was EML4-ALK fusion (V3a/b variants), indicating a poor prognosis. In this study, we analyzed the treatment efficacy of ALK inhibitors and provided a research basis for the treatment of EML4-ALK rearranged in lung squamous cell carcinoma patients.