Purpose: The aim of this study was to assess the evolution of health-related quality of Life (HRQoL), emotional burden, and neurocognitive function in the first-generation metastatic melanoma survivors treated with pembrolizumab. Methods: Survivors were defined as patients who achieved a durable remission for at least 6 months after initiating pembrolizumab in a single-center observational study (N = 141). A semi-structured interview was performed at baseline. Neurocognitive computerized testing and patient-reported outcomes were collected at 4 time points to assess HRQoL using the EORTC QLQ-C30 and the HADS to assess anxiety and depression. Results: Out of 35 eligible patients, 25 were recruited and completed baseline assessment (18 female; median age 58 years [range 28–86]; 24 completed the 1-year follow-up phase. Median time since diagnosis was 30 months (range 12–84); median time since initiation of pembrolizumab was 19 months (range 6–42). At all visits, survivors reported a significantly lower global HRQoL, lower physical, emotional, cognitive, role, and social functioning compared with the European Mean of the healthy population. Fifteen patients (64%) had clinical levels of anxiety/depression at one time point during follow-up. The clinical interview revealed that 12 patients (48%) suffered from Cancer-Related-Post-Traumatic-Stress disorder, of whom 7 (28%) developed transient suicidal ideation, 1 patient made a suicide attempt. Neurocognitive testing revealed cognitive impairment in 8 patients (32%). Conclusions: Metastatic melanoma survivors, treated successfully with pembrolizumab, are at risk for suffering from emotional distress and neurocognitive impairment with a persistent impact on their HRQOL. Timely detection in order to offer tailored care is indicated.