Metastatic unresectable malignant melanoma (MM) owing to its intrinsic biological invasion potential and low sensitivity to radiochemotherapy has a poor prognosis and a high rate of mortality; the mean survival period is only 6-8 months, and the 5-year survival rate is less than 10%. The progression of patients with brain and liver metastases is worse than those with other distant or visceral metastases. With the advent of immunotherapy, especially immune-checkpoint inhibitors, long-term remission of stage IV disease may be achieved in some patients. Despite recent advances, not all patients benefit or can afford immunotherapy. Here, we report the case of a 44-year-old man whose initial diagnosis was MM with liver and multiple brain metastases. A high expression of F-box/WD repeat-containing protein 7 (FBXW7) inactivating mutation was observed, and the patient was treated with a combination of everolimus and temozolomide (TMZ) following palliative radiotherapy. The patient was stable for approximately 17 months, and eventually showed an overall survival (OS) of about 19 months. This case is novel and instructional, which highlights that the combination of everolimus and TMZ might be effective, with manageable toxicity, for advanced MM patients with FBXW7 mutation. And it may provide a reference for the treatment of analogous patients.