Background: The timing of immune checkpoint inhibitor (ICI) administration may influence clinical outcomes, incidence, and severity of immune-related adverse events (irAEs), but evidence remains limited. Methods: We conducted a retrospective analysis of 41 patients with advanced melanoma treated with combined ipilimumab and nivolumab at the Istituto Oncologico della Svizzera Italiana between 2018 and 2024. Infusions completed before 2:00 p.m. were classified as morning (AM). Patients receiving ≥50% of doses in the morning were assigned to the AM group; the remaining patients comprised the afternoon (PM) group. Results: Twenty-one patients were included in the AM group and twenty in the PM group. Median progression-free survival (PFS) was not reached in the AM group, compared with 7.8 months in the PM group (univariate HR 0.29, 95% CI 0.12–0.70; p = 0.006). Overall survival (OS) was also significantly improved in the AM group (univariate HR 0.25, 95% CI 0.08–0.80; p = 0.019). The overall incidence of irAEs was similar between groups. However, systemic immunosuppression for grade ≥ 2 toxicities was more frequently required in the PM group (80% vs. 52%, p = 0.06). Conclusions: In this retrospective cohort, morning administration of ICIs was associated with improved PFS and OS in patients with advanced melanoma. While irAE incidence was comparable between groups, patients treated in the afternoon more often required systemic immunosuppression.