Background: Melanoma is a cancer of melanocytes and has the potential to metastasize to distant organs. Immune checkpoint inhibitors (ICI) enhance the immune response against cancer cells. Programmed cell death protein-1 (PD-1), PD-ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene (LAG-3) are the common targets of ICI. Blocking two pathways can have an additive/synergistic effect. This systematic review will assess the efficacy of two ICI combinations in cutaneous melanoma. Methods: A search was performed on PubMed, Embase, and clinicaltrials.gov. We used the following mesh and Emtree terms, “Melanoma” AND “Immune checkpoint inhibitors,” from the inception of literature till 01/15/2022. We screened 11,287 articles and included 4 randomized clinical trials (N = 1,948) and 6 single-arm clinical trials (N = 438) in this review. We excluded preclinical trials, case reports, case series, review articles, observational studies, meta-analysis, and irrelevant clinical trials. Results: In 10 clinical studies (N = 2,386), two ICI combinations were assessed in adult patients with melanoma. Nivolumab (nivo) + ipilimumab (ipi), relatlimab (rela) + nivo, pembrolizumab (pemb) + ipi, lag525 + spartalizumab (spa), fianlimab (fian) + cemiplimab (cem) and single drug/placebo were used to treat 560, 365, 223, 42, 48, and 1,148 patients, respectively. 2,119, 70, and 197 patients had advanced untreated, PD-1/L1 refractory, and resectable stage III/IV melanoma. The response rates (RR) and survival rates are given in table. Conclusions: Two ICI combinations of nivo, ipi, and rela were more effective than monotherapy in patients with untreated advanced melanoma. In early phase trials, combinations of ipi, nivo, pemb, lag525, spa, fian, and cem were effective in advanced melanoma. Nivo, ipi, and rela were effective in patients with resectable melanoma. Pemb+ipi was effective in patients with PD-1/L1 refractory melanoma. More randomized double-blinded clinical trials are needed to confirm these results.