Refractive index and density matching are essential for optical measurements of neutrally buoyant liquid−liquid flows. In this study, we proposed a design of experiments (DoE) to develop refractive index and density matching systems, including objective setting, candidates screening, sampling and fitting, and a detailed matching process. Candidates screening criteria based on the density and refractive index ranges of the aqueous and organic phases were used. Using the DoE, we proposed a system with a ternary aqueous phase potassium thiocyanate (KSCN)/ammonium thiocyanate (NH4SCN) solution and m-dichlorobenzene/tripropionin solution as the organic phase to achieve the tuning of the RI and density simultaneously. Empirical correlations of the refractive index and density with respect to the concentration and temperature for the three mixtures were obtained by combining Latin hypercube sampling with binary polynomial fitting. Correlations were validated with existing data in the literature and were found to align with deviations as low as 4×10−4 for the refractive index and 2×10−3 g⋅cm−3 for the density. Using the correlations, the refractive indices for the ternary aqueous phase, the binary organic phase, and the device materials were matched to be equal. Density matching was performed for the liquid−liquid phases as well. Refractive index- and density-matched recipes could be obtained for a wide range of temperatures (15−65 °C) and device materials (PMMA, borosilicate glass, quartz, and silica gel). These recipes provide options for the optical measurement of a liquid−liquid system required to neutralize buoyancy.