High-speed rotary ultrasonic elliptical milling (HRUEM), as a novel ultrasonic vibration cutting method, has been introduced in milling the alloy Ti-6Al-4V. The application of ultrasonic vibration in high-speed milling can help open the cutting contact area intermittently. New cutting effects will happen with full use of the separation effect brought by ultrasonic vibration and the cooling effect brought by a high-pressure coolant (HPC). On the basis of that, this paper firstly introduces HPC into HRUEM of Ti-6Al-4V in the open literature and analyzes the tool-workpiece separation cooling mechanism in HRUEM, including kinematic analysis of tool tip trajectories, tool-workpiece separation principles and high-pressure coolant effects. We have conducted a comprehensive experimental study and the results show when HPC is increased to 200 bar, compared to conventional milling (CM), the tool life in HUREM can be extended by 6.6 times at 80 m/min, 4.2 times at 120 m/min and 2.4 times at 160 m/min. The maximum material removal volume (MRV) for a given new end mill in HRUEM is increased by 657% approximately. When the cutting speed is 80 m/min, the cutting temperature of the workpiece in HRUEM is reduced by 24.1% compared to that of CM. By applying the combination of HPC and tool-workpiece periodic separation, we can significantly enhance the cooling and lubrication efficiency in HRUEM and also inhibit the tool wear mode of adhesive wear typically occurred in CM.