Many substrates for microelectronic systems contain ceramic/glass layers and metal features (e.g. electrodes, vias, metal pads) built up in a complex 3D architecture. The combination of different materials with distinct thermo-elastic properties may yield significant (local) internal stresses, which are to be superimposed to external thermo-mechanical loads in service. Due to the various material junctions, interfaces, etc, failure of these multilayer systems can hardly be predicted. In this work, a strategy is proposed to quantify the effect of architecture and loading conditions on the mechanical reliability of ceramic-based substrates. Model ceramic structures containing important design features (e.g. inner electrode, via, top metallization) were fabricated and tested in different environments (i.e. humid or dry conditions) under uniaxial as well as biaxial bending. Significant difference in the characteristic strength between ∼260 MPa and ∼620 MPa were measured, associated with the particular architectural feature, type of loading, and/or environment.