The treatment of metastatic melanoma has long posed a complex challenge within clinical practice. Previous studies have found that EMT transcription factors are essential in the development of various cancers through their induction of EMT. Here, we demonstrate that Snail2 expression is dramatically increased in melanoma and is associated with an adverse prognosis. Elevated Snail2 in melanoma cells enhanced migratory and invasive capabilities in vitro and in vivo. Furthermore, RNA-Seq analysis revealed a significant reduction of IGFBP3 expression in melanoma cells overexpressing Snail2. IGFBP3 might mitigate the Snail2's ability to promote melanoma metastasis via the PI3K-AKT pathway. Moreover, Snail2 and HDAC3 collaborate to suppress IGFBP3 transcription through H3K4 deacetylation and H4K5 delactylation. Additionally, the combination of HDAC3 and p-GSK-3β inhibitors significantly improved the treatment outcomes for lung metastasis in melanoma in vivo. The results of our study indicate that Snail2, HDAC3, and IGFBP3 play significant roles in melanoma progression and represent promising therapeutic targets.