Capillary leakage is a hallmark of severe dengue, yet its precise mechanisms remain elusive. Emerging evidence highlights the dengue virus's targeting of mechanically active endothelial cells as a key contributor to dengue shock syndrome. The viral nonstructural protein 1 (NS1) has been identified as a central player, disrupting endothelial integrity and inducing vascular hyperpermeability independently of pro-inflammatory cytokines. This study provides a direct assessment of NS1-induced endothelial pathology by combining single-cell force spectroscopy and a microvessel-on-a-chip platform. We demonstrate that NS1 significantly alters endothelial cell mechanics, reducing cell stiffness and compromising junctional integrity, thereby directly linking these mechanical alterations to vascular dysfunction. These findings establish a framework for understanding the mechano-pathology of dengue and offer a platform for developing targeted therapeutic strategies to mitigate severe disease outcomes.