Abstract The objective of this study was to find the role of LncRNA SNHG12 in the regulation of hypertensive vascular endothelial injury. LncRNA SNHG12 and miR-25-3p expression were detected by quantitative RT-PCR. Protein levels of Sirtuin 6 (SIRT6), endothelial cell (EC) senescence markers p16 and p21, and EC marker CD31 were measured by Western blot. The apoptosis of HUVECs was detected by flow cytometry. The binding between LncRNA SNHG12 and miR-25-3p was verified by dual luciferase reporter gene assay and RNA pull-down assay. As a result, LncRNA SNHG12 was down-regulated in aortic primary ECs isolated from Ang II-induced hypertensive mice and 1 kidney/deoxycorticosterone acetate/salt-induced hypertensive mice. In Ang II-treated HUVECs, the expression level of SNHG12 was reduced and the overexpression of SNHG12 inhibited EC senescence markers p16 and p21 expressions, the apoptosis of HUVECs, and caspase-3 activity. Further investigation confirmed that LncRNA SNHG12 bound to miR-25-3p, and negatively regulated miR-25-3p expression. MiR-25-3p directly targeted SIRT6 and negatively regulated SIRT6 expression. In addition, SNHG12 overexpression inhibited Ang II-induced HUVECs injury through regulating miR-25-3p. Finally, in vivo experiments showed LncRNA SNHG12 overexpression alleviated vascular endothelial injury in Ang II-induced hypertensive mice. In conclusion, LncRNA SNHG12 alleviates vascular endothelial injury induced by hypertension through miR-25-3p/SIRT6 pathway.