Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at‐site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I‐NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I‐NM@siRNA nanomedicine demonstrates effective at‐site siRNA release resulting from tumoral reactive oxygen species (ROS)‐triggered sequential destabilization. Furthermore, the utility of 3I‐NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I‐NM@siRNA nanomedicine with angiopep‐2 peptide is enhanced. The targeted Ang‐3I‐NM@siRNA exhibits superb blood–brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo‐like kinase 1 and vascular endothelial growth factor receptor‐2, Ang‐3I‐NM@siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple‐interaction stabilization together with inbuilt self‐destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases. A triple‐interaction‐stabilized small interfering RNA (siRNA) nanomedicine shows potent stability both in vitro and in vivo. When it encounters a reactive oxygen species (ROS) stimulus inside a tumor, the “triple‐interaction” stabilization forces can be sequentially neutralized, resulting in effective siRNA release. Moreover, on modification with angiopep‐2 peptide, the triple‐interaction‐stabilized siRNA nanomedicine demonstrates robust orthotopic glioblastoma combinational RNA interference therapy.