Abstract: A novel aero-structural performance validation methodology was proposed, namely, reverse iteration of structural model. This methodology aims to improve the aero-structural performance of cruise shape, and its efficiency can be improved by 4 times compared with conventional loosely-coupled aeroelastic analysis. A multidisciplinary design optimization methodology was proposed based on the above methodology, which aims to optimize the cruise shape directly. The optimization efficiency can be improved by 4 times with the proposed framework. The aerodynamic performance was predicted by N-S solver in this paper. Structural analysis was carried out by finite element analysis. All these analysis methods assured the design to be reliable. Test shows that the proposed aero-structural performance prediction methodology has the same fidelity with that of the conventional methodology. Aero-structural optimization design of an UAV based on the proposed framework validated the proposed methodology further.