Combination therapy with immune checkpoint inhibitors, specifically CTLA-4 and PD-1 blockade, has shown promise in treating advanced melanoma. However, this approach often results in increased toxicity, necessitating a careful evaluation of both efficacy and safety. This review explores clinical outcomes, survival rates, and adverse events associated with these therapies. A systematic review of PubMed, Scopus, and clinical trial databases was conducted for studies published from 2014 to 2024. Studies assessing the combined use of CTLA-4 and PD-1 inhibitors in melanoma patients were included, focusing on overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (AEs). The combination of CTLA-4 and PD-1 inhibitors significantly improved clinical outcomes in advanced melanoma. In trials like CheckMate 067, the five-year overall survival rate reached 52%, with a notable improvement in progression-free survival. However, these benefits came with substantial toxicity, as approximately 55% of patients experienced grade 3 or 4 treatment-related adverse events, including colitis, hepatitis, and pneumonitis. Despite these challenges, combination therapy led to durable responses in a subset of patients, underscoring its efficacy. The review emphasizes the need for balancing efficacy with toxicity management in clinical practice. While CTLA-4 and PD-1 inhibitor combinations improve survival in advanced melanoma, increased toxicity presents challenges. Further research is needed to optimize treatment strategies and enhance patient selection to balance efficacy and safety.