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<i>Metastasis-associated lung adenocarcinoma transcript 1</i> (<i>MALAT1</i>) and <i>multiple endocrine neoplasia-β</i> (<i>MENβ</i>) are two long noncoding RNAs upregulated in multiple cancers, marking these RNAs as therapeutic targets. While traditional small-molecule and antisense-based approaches are effective, we report a locked nucleic acid (LNA)-based approach that targets the <i>MALAT1</i> and <i>MENβ</i> triple helices, structures comprised of a U-rich internal stem-loop and an A-rich tract. Two LNA oligonucleotides resembling the A-rich tract (i.e., A₉GCA₄) were examined: an LNA (L15) and a phosphorothioate LNA (PS-L15). L15 binds tighter than PS-L15 to the <i>MALAT1</i> and <i>MENβ</i> stem loops, although both L15 and PS-L15 enable RNA•LNA-RNA triple-helix formation. Based on UV thermal denaturation assays, both LNAs selectively stabilize the Hoogsteen interface by 5–13 °C more than the Watson–Crick interface. Furthermore, we show that L15 and PS-L15 displace the A-rich tract from the <i>MALAT1</i> and <i>MENβ</i> stem loop and methyltransferase-like protein 16 (METTL16) from the METTL16-<i>MALAT1</i> triple-helix complex. Human colorectal carcinoma (HCT116) cells transfected with LNAs have 2-fold less <i>MALAT1</i> and <i>MENβ</i>. This LNA-based approach represents a potential therapeutic strategy for the dual targeting of <i>MALAT1</i> and <i>MENβ</i>.