The flexible piezoelectric energy harvester (FPEH), as an effective strategy for long-term power supply of implantable and wearable electronics, requires high areal output energy density, low mechanical stiffness, and high energy efficiency, simultaneously. The widely adopted sandwich FPEH, consisting of one relatively hard substrate sandwiched between two piezoelectric films, can provide a high areal output energy density, but also high mechanical stiffness and low energy efficiency due to its energy-wasting deformation of the hard substrate. Here, we propose a novel optimal soft-substrate sandwich FPEH with designs of sufficient length and optimized Young’s modulus of the substrate, which is much smaller than that of the piezoelectric film. A sandwich beam model considering both the bending and shearing of the soft substrate and the one-way coupling of the piezoelectric effect was adopted for the theoretical analysis and optimal design. The optimal soft-substrate sandwich FPEH exhibits greatly improved overall performance with a 33% increase in areal output energy density, a 51% reduction in mechanical stiffness, and a 177% increase in energy efficiency, simultaneously. Systematic theoretical analysis is performed to illustrate the mechanism and guide the optimal design. The novel optimal soft-substrate sandwich FPEH is then applied to harvesting energy from various living subjects. This optimal design can be extended to other types of mechanical energy harvesters with a similar laminated structure.