Three-way spatial fluid channel (TSFC) is commonly used in spatial fluid channels of the high hydraulic integrated system. However, the mathematic model of TSFC pressure loss is not clear, and what TSFC structural parameters in a certain space can get the minimum pressure loss and weight is also vague. Therefore, TSFC pressure loss mathematic model and multi-objective optimization about pressure loss, axis path length, and mass are studied in this paper. First, the mathematic model of TSFC pressure loss is established based on the response surface methodology and pressure loss models of fluid dynamics. Then, the optimized mathematic model for the TSFC structural parameters is built by the multi-objective optimization design method to achieve low pressure loss, short axis path length, and lightweight. According to the simulation, the results of optimized structure model show that the mass has been reduced 5.68%, and the pressure loss has been reduced 70.75% compared with the original model. Besides, the optimized TSFC structure model is manufactured by additive manufacturing, and the experiment is carried out to measure TSFC pressure loss. It shows that the error of pressure loss between the mathematic model and the experiment is only 1.6%, which verifies the accuracy of mathematic model of the pressure loss. This research lays a foundation for the design and optimization of the spatial flow channel in highly integrated hydraulic systems.