Indium Tin Oxide (ITO) films are widely used as transparent electrodes in electronic displays and solar cells. However, the small fracture strain of brittle ITO films poses significant challenge to their applications in flexible electronics devices that often undergo large deformation. Inspired by recent development of inorganic/organic hybrid permeation barriers for flexible electronics, we design and fabricate ITO-based multilayer electrodes with enhanced electro-mechanical durability. In situ electro-mechanical experiments of five structural designs of ITO-based multilayer electrodes are performed to investigate the evolution of crack density and the corresponding variance of electrical resistance of such electrodes. A coherent mechanics model is established to determine the driving force for crack propagation in the ITO layer in these electrodes. The mechanics model suggests that a top protective polymeric coating above and an intermediate polymeric layer below the ITO layer can effectively enhance the mechanical durability of the ITO electrodes by reducing the crack driving force up to 10-folds. The modeling results offer mechanistic understanding of the in situ experimental measurements of the critical fracture strains of the five types of ITO-based multilayer electrodes. The findings in this work provide quantitative guidance for the material selection and structural optimization of ITO-based multilayer transparent electrodes of high mechanical durability.