Endovascular guidewire interventional surgery is an effective treatment for vascular diseases. However, due to factors, such as blood viscosity and complex vascular morphology, the guidewire is interfered by strong varying resistance when moving in the lesion’s vasculature. This greatly affects the efficiency and safety of the clinical operation. Here, we develop a novel system that applies ultrasonic micro-amplitude vibration to the conventional passive guidewire for studying a drag reduction effect under multiple factors. The system is mainly composed of a sandwich-type ultrasonic transducer and a step-type horn for concentrating the unidirectional energy for micro-vibration. Subsequently, comparative experiments are designed to verify the effectiveness of this system for drag reduction. Through the multifactorial interactions, we study the friction reduction law of the microvibration-assisted method on the guidewire and the optimal drag reduction parameter combinations. The results show that the drag reduction effect varies with the amplitude–frequency response curve. An ultrasound vibration amplitude and a simulated vessel bending angle were the most significant factors. Only vibration frequency and amplitude interacted with a simulated vessel shape. Finally, using the resonance frequency and the maximum vibration amplitude to drive the guidewire vibration, the maximum friction reduction rate can be obtained, up to 85.2%. This system is expected to have important applications in clinical vascular interventional procedures.