As the core component of the aircraft engine, high-efficiency manufacture of blisk is very difficult, because of its complex structure, high precision, and whose material belonging to difficult-to-machine materials such as titanium alloy, high temperature alloy and so on. It is one of the effective methods to solve the above problems by applying the side milling technology to the manufacture of blisk; the design and manufacture of ball end milling tool and the optimization of cutting parameters are of great significance to the advantage of the side milling process. Firstly, by analyzing the sectional line of tool, the mathematic models of tool edge line and tool escape curve are established. Based on these models, the parameterized model of the tool is finished, which paves the way for the subsequent analysis and optimization of the tool. After optimization, it is found that the ball end milling tool with a rake angle of 10°, a first rear angle of 12°, and a spiral angle of 38° has the best cutting effect on titanium alloy; secondly, the finite element method is used to design and analyze the geometrical structure of tool, and the modal analysis of the tool is carried out by DEFORM-3D to ensure the stability of cutting process, and the designed tool was manufactured by using the tool grinder; finally, the experimental research on the side milling titanium alloy was carried out by using the manufactured tool, and the influence of cutting parameters on the cutting force and the surface roughness was analyzed, and the model of cutting force and surface roughness and machining efficiency is completed. Based on the NSGA-II algorithm, the multi-objective optimization of the cutting parameters with cutting force, surface roughness, and metal removal rate as index is completed; the optimized results are as follows: vc = 70.2 m/min, fz = 0.03 mm/z, ae = 0.7 mm, and the axial depth is ap = 7.6 mm. This set of cutting parameters can guarantee small surface roughness and high machining efficiency under the condition of small cutting force, which is expected to provide a better theoretical reference and technical support for the tool design and high efficient manufacture of blisk.