Vortex-induced vibration (VIV) of bluff bodies is one type of flow-induced vibration phenomenon, and the possibility of using it to harvest hydrokinetic energy from marine currents has recently been revealed. To develop an optimal harvester, various parameters such as mass ratio, structural stiffness, and inflow velocity need to be explored, resulting in a large number of test cases. This study primarily aims to examine the validity of a parameter optimization approach to maximize the energy capture efficiency using VIV. The Box–Behnken design response-surface method (RSM-BBD) applied in the present study, for an optimization purpose, allows for us to efficiently explore these parameters, consequently reducing the number of experiments. The proper combinations of these operating variables were then identified in this regard. Within this algorithm, the spring stiffness, the reduced velocity, and the vibrator diameter are set as level factors. Correspondingly, the energy conversion efficiency was taken as the observed value of the target. The predicted results were validated by comparing the optimized parameters to values collected from the literature, as well as to our simulations using a computational-fluid dynamics (CFD) model. Generally, the optimal operating conditions predicted using the response-surface method agreed well with those simulated using our CFD model. The number of experiments was successfully reduced somewhat, and the operating conditions that lead to the highest efficiency of energy harvesting using VIV were determined.