This study measures and analyzes the void fraction of R454C, a zeotropic refrigerant, using a capacitance-based sensor. Capacitance-based sensors offer an attractive method for real-time void fraction measurement. Given that zeotropic refrigerants undergo compositional changes in their gas and liquid phases during phase change, it is essential to account for variations in relative permittivity due to these compositional changes when using a capacitance-based sensor for void fraction measurement. In this study, Landau and Lifshitz’s mixing rule is employed to predict the relative permittivity based on compositional variations of a bi-component refrigerant, along with a calibration strategy for the capacitance-based sensor based on flow pattern transitions. The void fraction measurement results obtained from the capacitance-based sensor for R454C are validated by comparison with results obtained using the quick-closing valve-based (QCV) method under identical conditions. The measurement uncertainty of the developed sensor is 4.13 %, and compared to the measurement results from the QCV method, it is found to have a relative error of −0.955 % over the entire range of experimental conditions. The measurements are conducted in a smooth tube with an inner diameter of 7.1 mm, mass flow rates ranging from 100 to 400 kg m−2 s−1, pressures from 0.789 to 1.724 MPa, and inlet vapor quality from 0.025 to 0.900. The measurement results are then compared with existing prediction correlations, and those correlations offering acceptable predictions of the void fraction of R454C are presented.