Thoracic aortic aneurysm/dissection (TAA/D) is a complicated vascular disorder with galloping development and high mortality. Phenotype switching plays an important role in the pathological process of TAA/D. Previous studies indicated the potential correlation between the expression level of lncRNA RP11-465L10.10 and MMP9 involved in the development of TAA/D. Here, our results showed that RP11-465L10.10 and MMP9 were highly increased in TAD patient tissues, which was consistent in Ang II-induced vascular smooth muscle cell (VSMC) phenotype switching. However, the effects and underlying mechanism of RP11-465L10.10 on VSMC phenotypic switching remain uncertain. Therefore, the expression of SM22α, cell proliferation, and migration were investigated when ectopically expressed RP11-465L10.10 in VSMCs. The results showed that RP11-465L10.10 overexpression decreased SM22α expression and facilitated VSMC proliferation, migration, and MMP9 expression. Furthermore, the NF-κB signaling pathway was enriched in transcriptome data analysis, indicating that NF-κB signaling may be involved in RP11-465L10.10-induced VSMC phenotype switching and MMP9 expression. In conclusion, this study demonstrated that RP11-465L10.10 induces VSMC phenotype switching and MMP9 expression via the NF-κB signaling pathway, suggesting that RP11-465L10.10 might be a potential therapeutic target for TAA/D treatment.