During high-power laser treatment, protection of the epidermis and normal tissues from thermal damage is critical to ensure safety and effectiveness of the process. In this investigation, medical 134a cryogen with high cooling performance was used, and a high-pressure storage tank, an airtight transmission line, a high-speed atomized spray device, and an electronic control system were designed as part of a transient spray cooling system combined with laser therapy for different output timings to cool the skin and tissue in real-time. By studying the relationship between the spraying time, jet distance, and temperature changes of materials that are similar to skin, the cooling effect of the device was evaluated. The experimental results show that the tissue temperature can be reduced from 40 ℃ to 60 ℃ in 20 ms to 50 ms. The biological compatibility, pressure resistance, and sealing of the cooling system met the requirements of medical device registration. The system was combined with a high-power 1 450 nm semiconductor laser to treat facial acne in a clinical setting, and the total effective rate for 189 patients with mild-to-moderate acne is 87.3% after four treatments without thermal damage. It is possible to combine the transient spray cooling system with various laser devices to improve the safety, effectiveness, and scope of existing laser treatments.