The complex flow structure and interfacial effect in oil–gas–water three-phase flow have made the void fraction measurement a challenging problem. This paper reports on the void fraction measurement of oil–gas–water three-phase flow using a mutually perpendicular ultrasonic sensor (MPUS). Two pairs of ultrasonic probes are installed on the same pipe section to measure the void fraction. With the aid of the finite element method, we first optimize the emission frequency and geometry parameters of MPUS through examining its sensitivity field distribution. Afterward, the oil–gas–water three-phase flow experiment was carried out in a vertical upward pipe with a diameter of 20 mm to investigate the responses of MPUS. Then, the void fraction prediction models associated with flow patterns (bubble flow, slug flow, and churn flow) were established. Compared to the quick closing valves, MPUS obtained a favorable accuracy for void fraction measurement with absolute average percentage error equaling 8.983%, which indicates that MPUS can satisfactorily measure the void fraction of oil–gas–water three-phase flow.