Multilayer metallic interlayers with two different architectures, one Nb-based and the other V-based, both designed to produce a thin transient-liquid-phase layer, have been used to bond high-purity Al2O3 ceramics. The mechanical properties of the resulting Al2O3-metal joints were examined at both macro- and nano-scale levels. The roles of the interlayer designs (Ni/Mo/Nb/Mo/Ni vs. Ni/Nb/V/Nb/Ni), resulting joint microstructures, lattice defects, and residual stresses on mechanical properties and failure modes were evaluated. Reduced residual stresses and improved ceramic/metal interfacial microstructures contribute to the superior performance obtained with the Ni/Mo/Nb/Mo/Ni multilayer interlayer.