Background/Objectives: Metastatic uveal melanoma (mUM) carries a poor prognosis and limited systemic treatment options. While immune checkpoint inhibitors have improved outcomes in cutaneous melanoma, their activity in mUM remains modest. Tebentafusp has recently emerged as the first therapy to improve overall survival in HLA-A*02:01–positive patients, but effective options for others remain scarce. This study compared the real-world effectiveness and safety of ipilimumab plus nivolumab versus anti-programmed cell death protein 1 (PD-1) monotherapy. Methods: We conducted a retrospective single-center analysis of patients with mUM treated at the National Institute of Oncology, Budapest. Patients received either dual checkpoint inhibition (ipilimumab plus nivolumab) or anti-PD-1 monotherapy (nivolumab or pembrolizumab). Evaluated outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and immune-related adverse events (irAEs). Survival was analyzed using Kaplan–Meier methods, log-rank tests, and Cox regression. Results: Fifty-five patients were included (33 ipilimumab–nivolumab, 22 anti-PD-1). ORR was 21% versus 5%, and DCR was 42% versus 32%, respectively. Median PFS was 5.8 vs. 3.7 months (p = 0.053; HR 0.61, 95% CI 0.34–1.09), and median OS was 12.3 vs. 10.6 months (p = 0.214; HR 0.66, 95% CI 0.36–1.22). Grade 3–4 irAEs occurred in 48% of patients receiving ipilimumab–nivolumab compared with 9% on monotherapy. No treatment-related deaths were observed. Conclusions: Anti-PD-1 monotherapy demonstrated limited clinical activity, providing little benefit beyond conventional chemotherapy. Dual checkpoint blockade with ipilimumab and nivolumab achieved higher response and disease control rates, albeit with increased toxicity, suggesting a potential benefit for selected patients. Tebentafusp has emerged as an effective option and a new standard of care for a molecularly defined subgroup of HLA-A*02:01–positive patients. However, for the majority of individuals with metastatic uveal melanoma, effective systemic therapies remain an unmet need.