This paper presents the design and optimization of a novel piezoelectric energy harvester with a single piezo-stack for harvesting energy from excitations with 3-DOF direction. To scavenge the energy with 3-DOF direction of input force, the proposed energy harvester is composed of a two-stage force amplifier with single piezo-stack, several force transmission mechanisms, and slider mechanisms. Analytical model is established to predict the force amplification ratio of the proposed energy harvester. In order to maximize the output performance of the proposed energy harvester, key parameters of the mechanism are selected and optimally designed. Optimization result indicates that the developed harvester has the merits in terms of high safety factor, large force-amplification ratio, and compact size.