An application of cyber-physical testing to the empirical estimation of difference-frequency quadratic transfer functions is presented. As an alternative to today’s procedure based on hydrodynamic tests with broad-banded or realistic (e.g., JONSWAP) wave spectra, tests in bichromatic waves are considered. The laboratory setup is the one developed by Sauder & Tahchiev (2020) that enables magnifying the sensitivity of the floater response to the low-frequency wave loading by adjusting the stiffness and damping parameters of a virtual soft mooring system. Bayesian experimental design is proposed to optimize the selection of the control variables (frequencies in the bichromatic wave and properties of the virtual mooring system) for a batch of cyber-physical tests. The experimental design algorithm is based on the recent work of Huan & Marzouk (2013). In a virtual yet realistic case study using an uncertain parametric quadratic transfer function, we demonstrate how the uncertainty of its describing parameters and other calibration parameters (low-frequency added mass and hydrodynamic damping) can be reduced. Results indicate that the proposed procedure has the potential for reducing experimental cost for calibration of hydrodynamic models.