With a low boiling point (−45.5 °C at 1 atm) and high volatility, cryogen R-404a has the potential to replace current R-134a (−26.1 °C at 1 atm) for improved therapeutic outcome of dark skins in cutaneous laser treatment. This paper presents an experimental study on pulse spray cooling with cryogen R-404a including the spray characteristics and the resulting dynamic cooling of a solid surface. The spray system includes a special designed pressure nozzle (with the tube diameter less than 1 mm) that is connected to a fast response electric valve which can open or close within 5 ms. A high-speed video camera is used to obtain images of the spray pattern. The velocity and the diameter of the liquid droplets in spray are measured by the phase Doppler particle analyzer (PDPA). A thin film thermocouple of 2 μ in thickness is directly deposited on the epoxy resin substrate to monitor rapid drop of the surface temperature under the pulsed sprays. The Duhamel’s theorem is then solved to obtain the time-varying surface heat flux and heat transfer coefficient of the substrate surface. It is found that the large droplet size together with fairly high-speed in the early jet-like spray leads to highly efficient surface cooling.