Background: Approximately 40–50% of Stage IV melanoma patients eventually develop brain metastases which is associated with poor prognosis. Breakthroughs in targeted and immunotherapies have improved long-term survival in advanced melanoma patients. In this new era, there is a paucity of evidence for the role of metastatectomy for melanoma patients with brain metastasis. Here, we investigate the survival benefit of metastasectomy and primary site resection in melanoma patients with isolated brain metastasis. Methods: A total of 636 patients with melanoma with isolated brain metastasis at diagnosis were extracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2019. Patients younger than 18 years, cases with missing information including age, gender, race, unknown stage, unknown primary site resection status, unknown metastasis site, or known metastasis to the lung, liver, or bones were excluded. Cox regression analysis estimated the prognostic value of metastasectomy and primary site resection, presented by hazard ratios (HR), among melanoma patients. Survival ratios were controlled for age, race, gender, and type of melanoma. All analyses were performed on STATA v17. Results: About 49.37% of melanoma patients with isolated brain metastasis underwent metastasectomy. Of the included sample, 25% (n = 159) underwent primary site resection. Cox regression demonstrated that metastasectomy was associated with improved survival outcomes in melanoma patients with isolated brain metastasis (HR 0.51, CI 0.42 – 0.63, p < 0.001). Pooled primary site resection procedures were associated with improved survival (HR 0.64, CI 0.49 – 0.83, p = 0.001) compared to not having a primary site resection. When stratified per procedure type, “wide excision or re-excision of lesions with margins > 1 cm and microscopically negative margins” was associated with improved survival (HR 0.27, CI 0.133 – 0.56, p < 0.001) compared to not having surgical resection, all other primary site resection procedures had no significant improvement in survival with p > 0.05. Conclusions: Metastasectomy and primary site resection significantly improved survival in melanoma patients with isolated brain metastasis. Wide excision with > 1cm negative margins presents itself as the most effective surgical treatment modality in terms of improving survival for these patients. Thus, it should be attempted whenever feasible.