Background: Despite the successful treatment of primary uveal melanoma (UM), metastasis occurs in up to half of the patients with UM. To delay metastasis for high-risk patients with UM, adjuvant therapy with sunitinib malate or valproic acid (VPA) is used. Therefore, assessing and addressing quality of life (QOL) during adjuvant therapy is essential to mitigate interferences that may prevent these patients from adherence to the therapy protocol and impair their well-being. The objective of this study is to analyze the QOL of these patients during adjuvant therapy with sunitinib or VPA, and to explore differences by the type of adjuvant therapy, age, sex, and the duration of adjuvant therapy. Methods: We analyzed longitudinal surveys of the FACT-G completed by high-risk patients with UM who participated in the randomized phase II clinical trial cohort 1 receiving 6 months of adjuvant sunitinib or VPA and Cohort 2 receiving 12 months of adjuvant sunitinib at a single center. Data were obtained before the initiation of adjuvant therapy and at 1, 3, and 6 months in cohort 1 and at 1, 3, 6, 9, and 12 months in cohort 2. We examined whether there were associations of QOL with the type of adjuvant therapy, age category, sex, and the time of adjuvant therapy using generalized estimating equations (GEE) modeling under the autoregressive working correlation structure (AR1) indexed within subjects by time. Results: There were 720 survey responses collected from 149 UM patients. In our sample, 70.4% (Cohort 1a, n = 45 and Cohort 2, n = 60) were treated with sunitinib and 29.5% (Cohort 1b, n = 44) with VPA. There was no significant difference in the QOL between the sunitinib group 1a and the VPA group 1b (p = 0.958). There was no significant difference in the overall QOL by age range (p = 0.093). However, participants aged 18 to 44 years had significantly lower emotional well-being mean scores (15.32, 95% Cl [13.53, 17.11]) compared to participants aged 65 years and above (19.06, 95% Cl [18.27, 19.86], p < 0.001) but no significant difference with participants aged 45 to 64 years (18.35, 95% Cl [17.53, 19.16], p = 0.193). There was no significant difference in the QOL by sex (p = 0.863) or trend in overall QOL means scores over time as the estimated slope of 0.02 QOL units per month was not significant (95% CI [-0.35, 0.38], p = 0.94). Conclusions: In our high-risk patients with UM, the type of adjuvant therapy, age, sex, and time of adjuvant therapy were not significantly differentiating factors for the QOL scores. Participants aged 18 to 44 years had significantly lower emotional well-being scores. We did not find enough evidence to suggest that there was a change in QOL during adjuvant therapy with sunitinib or VPA.