Background: Despite successful treatment of primary uveal melanomas, up to 50% of patients subsequently develop systemic metastasis, with the liver involved in up to 90% of patients. At our institution, recognition of the poor prognosis associated with liver metastasis has led to the use of various liver-directed treatment modalities including transarterial chemoembolization (TACE) with BCNU, drug-eluting beads with doxorubicin (DEBDOX), immunoembolization (IE) with GM-CSF, and radioembolization with Yttrium 90 radioactive microspheres. The purpose of this study is to compare overall survival between uveal melanoma patients with hepatic metastasis before and after the shift of initial treatment from systemic to liver-directed approaches. Methods: A retrospective single-institution chart review was performed on consecutive series of uveal melanoma patients with hepatic metastasis who were treated at Thomas Jefferson University between 1971–1993 (Cohort 1, n = 98) and 2000–2017 (Cohort 2, n = 634). The following data was collected from medical records: primary tumor stage and genetic abnormalities, primary eye treatment, date to hepatic and extra-hepatic metastasis, types of liver-directed and systemic treatments utilized, and date of death. Time from development of hepatic metastasis to death (OS-Liver) and time from initial treatment of primary uveal melanoma to death (OS-Eye) in individual cohorts were measured and analyzed. Results: 81% of cohort 1 patients received systemic chemotherapy as their initial treatment for liver metastasis, while 91% of cohort 2 patients (n = 574) initially received liver-directed treatments including IE (n = 296), BCNU TACE (n = 147), DEBDOX (n = 45), radioembolization (n = 37), and other liver-directed treatments (n = 49). OS-Liver in cohort 1 and cohort 2 was 4.8 months and 16.4 months, respectively (P < 0.001). More importantly, OS-Eye in cohort 2 (5.1 years) is much longer than that of cohort 1 (3.3 years) (P < 0.001). Conclusions: Liver-directed treatments provided significant survival benefit for uveal melanoma patients with hepatic metastasis.