MAPK-pathway up-regulation is responsible for over 40% of human cancer cases. Finding effective therapeutic targets for melanoma therapy continues to be a challenge due to drug resistance. Using a computational and experimental pipeline, we discovered the nuclear enriched long non-coding RNA (lncRNA) TRASH, which is induced upon MAPK-pathway-activation in melanoma. LncRNA hold essential regulatory functions in many cancer types. TRASH-targeting Antisense Oligonucleotides (TRASH-ASOs) greatly reduced cell-growth of melanoma cells in culture and systemic TRASH-ASO treatment significantly inhibited tumor growth of melanoma cell-line and patient-derived tumor xenografts without apparent side effects. We found that TRASH is essential for protein stability of the MAPK-pathway-regulating and apoptosis-inhibiting oncogene hnRNPA2/B1. TRASH knockdown induced apoptosis by down-regulating anti-apoptotic kinase activity and pro-survival signaling pathways. Compared to the well-studied oncogenic lncRNA MALAT1, the unique feature of TRASH is that it governs tumor cell-survival through maintaining activity of anti-apoptotic kinases and pro-survival signaling pathways in melanoma cells. TRASH-ASO treatment can bypass MEK-inhibitor (MEKi) resistance, and unlike MEKi, it does not induce early-onset treatment resistance. Furthermore, TRASH-ASO and MEKi combinations confer synergistic effects in melanoma treatment. Our findings show that TRASH-ASO treatment presents promising features for long lasting RNA-targeting melanoma therapy.