Abstract: The shape machining of carbon fiber reinforced polymer (CFRP) flexible parts is an important process in manufacturing of high-end aerospace equipment. Reliable clamping of the flexible parts is a prerequisite to control the deformation and reduce the dimensional deviation in machining. Firstly, the basic conditions for clamping and friction constraint by theory analysis were given, and a principle of “Following the shape and near the point” for the sucker distribution based on the cantilever beam theory was proposed. Furthermore, based on the “ISIGHT-ABAQUS” co-simulation method, the simulation analysis of the deformation of the CFRP flexible part were taken under different clamping conditions. The research shows that the elastic deformation of the vacuum sucker is easy to increase the clamping deformation, and the combination of the vacuum and positioning suckers should be used. When the numbers of the positioning suckers are 8, 12, or 16, and are distributed according to the principle of “Following the shape and near the point”, the influence of the distribution of the vacuum sucker on the deformation of the flexible part is negligible. Finally, the machining size deviation when considering the positioning geometric deviation was analyzed by the simulation and experiment. The trends in simulation and experiment are consistent with each other, and after the clamping optimization the dimension deviation can be reduced by 57.7 μm (35%). In summary, the machining dimension deviation caused by the deformation in shape machining of CFRP flexible parts cannot be ignored, and then the clamping optimization under the proposed principles of “Following the shape and near the point” and “Combining of positioning and vacuum suckers” can greatly reduce the dimension deviation caused by the deformation.