Melanoma patients failing all approved treatment options have a poor prognosis. The antimelanoma activity of regorafenib (REGO), a multitargeted kinase inhibitor, has not been investigated in this patient population. The objective response rate and safety of REGO treatment in advanced melanoma patients was investigated retrospectively. Twenty-seven patients received REGO treatment. All patients had progressed on anti–programmed cell death protein 1 (PD-1) and anti–cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) checkpoint inhibition and BRAF/MEK inhibitors (in case of a BRAF  V600mutation). REGO was administered in continuous dosing and combined (upfront or sequentially) with nivolumab (n = 5), trametinib (n = 8), binimetinib (n = 2), encorafenib (n = 1), dabrafenib/trametinib (n = 9), or encorafenib/binimetinib (n = 7). The best overall response was partial response (PR) in five patients (18.5%) and stable disease in three patients (11.1%). Three of seven (42.8%) BRAF   V600mut patients treated with REGO in combination with BRAF/MEK inhibitors obtained a PR (including regression of brain metastases in all three patients). In addition, PR was documented in a BRAF  V600mut patient treated with REGO plus anti-PD-1, and a NRAS Q61mut patient treated with REGO plus a MEK inhibitor. Common grade 3–4 treatment-related adverse events included arterial hypertension (n = 7), elevated transaminase levels (n = 5), abdominal pain (n = 3), colitis (n = 2), anorexia (n = 1), diarrhea (n = 1), fever (n = 1), duodenal perforation (n = 1), and colonic bleeding (n = 1). Median progression-free survival was 11.0 weeks (95% confidence interval, 7.1–14.9); median overall survival was 23.1 weeks (95% confidence interval, 13.0–33.3). REGO has a manageable safety profile in advanced melanoma patients, in monotherapy as well as combined with BRAF/MEK inhibitors or PD-1 blocking monoclonal antibodies. The triplet combination of REGO with BRAF/MEK inhibitors appears most active, particularly in the BRAF  V600mut patients.