A high vacuum environment safeguards the performance of special processing technologies and high-precision parts such as nanosecond laser processing, chip packaging, and optical components. However, it poses higher requirements for the machine tool, which makes the temperature control of machine tools an important goal in design and development. In this paper, the thermal properties of a large-scale 5-axis laser processing machine tool in a vacuum environment were investigated. The thermal contact resistance between parts is identified by the parametric simulation and experiment. The whole machine temperature field was then obtained based on the fluid–thermal coupling model and verified by experiment. The results showed that the thermal contact resistance of the motor and reducer with the water cold plate was 560 W/(m²∙°C) and 510 W/(m²∙°C), respectively, and the maximum temperature increase of the machine was 3 °C. Based on the results, the machine tool’s temperature increase prediction chart was obtained by simulation under different processing conditions such as cooling water flow rate, cooling water temperature, motor speed, and ambient temperature. It provides technical and data references for the research on the thermal stability of the machine tool in processing.