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Simple Summary Approximately 60% of all melanomas are associated with a constitutive activating BRAF mutation. Inhibition of BRAF downstream signaling by targeted therapies significantly improved patient outcomes. However, most patients eventually develop resistance. Here we identified miR-129-5p as a novel tumor suppressor in BRAF mutated melanoma, which expression is increased during response to BRAF inhibition, but repressed in an EZH2 dependent manner during activated BRAF signaling. Overexpression of miR-129-5p decreases melanoma cell proliferation and improves response to BRAF inhibition by targeting SOX4. Taken together our results emphasize SOX4 as a potential therapeutic target in BRAF driven melanoma which could be attacked by pharmaceutically. Abstract Many melanomas are associated with activating BRAF mutation. Targeted therapies by inhibitors of BRAF and MEK (BRAFi, MEKi) show marked antitumor response, but become limited by drug resistance. The mechanisms for this are not fully revealed, but include miRNA. Wishing to improve efficacy of BRAFi and knowing that certain miRNAs are linked to resistance to BRAFi, we wanted to focus on miRNAs exclusively associated with response to BRAFi. We found increased expression of miR-129-5p during BRAFi treatment of BRAF- mutant melanoma cells. Parallel to emergence of resistance we observed mir-129-5p expression to become suppressed by BRAF/EZH2 signaling. In functional analyses we revealed that miR-129-5p acts as a tumor suppressor as its overexpression decreased cell proliferation, improved treatment response and reduced viability of BRAFi resistant melanoma cells. By protein expression analyses and luciferase reporter assays we confirmed SOX4 as a direct target of mir-129-5p. Thus, modulation of the miR-129-5p-SOX4 axis could serve as a promising novel strategy to improve response to BRAFi in melanoma.