Helical milling is a new processing method for assembly hole in aerospace field. Compared with the traditional drilling technology, helical milling has many advantages, such as good processing quality, high drilling efficiency, low tool cost. During the process of helical milling in machining carbon fiber reinforced polymer (CFRP) /titanium alloy (Ti) stacks, due to the huge difference between the two materials, there is a hole diameter deviation between the two layers, which affects the hole making accuracy and becomes an urgent problem to be solved in the application process of helical milling technology. A helical milling test device was built, and the helical milling test of CFRP/Ti stacks was carried out. According to the test results, the causes of the hole diameter deviation between layers of CFRP/Ti were analyzed. The method of restraining the hole diameter deviation between layers was proposed based on changing parameter processing and milling method. Finally, the confirmatory test was carried out and the results show that the hole diameter deviation between layers in helical milling of CFRP/Ti could be effectively reduced by using the variable parameter machining method, which is less than 0.02 mm.