The work aims to soundly design cutting parameters of titanium alloy machined parts, including cutting depth, feed per tooth and spindle rotation speed in helical milled hole for difficult-to-cut materials. A set of testing program was formulated and carried out based on orthogonal optimization method. Roughness measuring instrument, coordinate measuring machine and microscope were used to measure and analyze surface roughness (Ra), diameter accuracy of titanium alloy hole and burr height at outlet end. On this basis, horizontal range and contribution rate of influencing factors were analyzed by combining with experimental data, and then a set of cutting parameters was selected (spindle rotation speed of 2000 r/min, feed per tooth of 0.07 mm and cutting depth of 0.25 mm/r). Then the surface roughness of titanium alloy workpiece to be machined was predicted. The titanium alloy machined part was tested and anlyzed in order to verify if the predicted value conformed to surface quality standards of the hole. Surface roughness of helical milled hole ranged from 0.55 to 0.75 μm while diameter accuracy was within H7 and H9, well meeting the technical requirements for drill hle roughness in aerospace or automobile industry. Therefore, not only cutting parameters in robust design are obtained by using this method, but also cutting technology of titanium alloy helical milled hole is improved.