The gut microbiome is an established predictor of response to immune checkpoint inhibitors (ICI) in melanoma, and antibiotic exposure prior to ICI initiation is a validated negative prognostic factor. About half of melanoma patients harbor BRAF mutations and are treated with BRAF/MEK inhibitors (BRAFi/MEKi). While the detrimental impact of antibiotics is well described in the ICI setting, their effect on BRAFi/MEKi efficacy remains unknown. We retrospectively analyzed 49 advanced BRAF-mutant melanoma patients treated with BRAFi/MEKi. Antibiotic-exposed patients were compared with non-exposed patients across three time windows: within 30, 60, or 90 days before and after therapy initiation. Outcomes included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). Among the cohort, 41% had antibiotic exposure within ±30 days, 53% within ±60 days, and 57% within ±90 days. Baseline characteristics were comparable between groups, except for worse ECOG scores in antibiotic-exposed patients. Across all windows, ORR, PFS, and OS were comparable between groups. Unlike what was observed in the ICI setting, antibiotic use did not negatively affect outcomes with BRAFi/MEKi. Despite small sample size, these findings suggest that the detrimental prognostic impact of antibiotics is specific to immunotherapy, highlighting the importance of evaluating the microbiome as a predictive biomarker across treatment contexts.