To better understand the method for determining the optimal measurement area of a computerized numerical control （CNC） machine tool in-machine measurement system with different measurement objects and universal application， a ball is selected as the measurement object， and the working principle and error sources of the in-machine measurement system are analyzed. A single error-whitening model is established using a dual-frequency laser interferometer and a beetle antenna search algorithm backpropagation （BAS-BP） neural network measurement. Simultaneously， the comprehensive error model of the measurement system and the spherical measurement error model are established. The differential evolution cuckoo search （DE-CS） algorithm for determining the optimal measurement area search is studied. The search performances of different algorithms are compared， and the optimal performance parameters of the algorithm are determined. An experimental device is set up to determine the optimal measurement area of the sphere， and the corresponding experiments are carried out. Finally， the consistency of the optimal measurement position determined by the algorithm and the actual measurement is compared. The experimental results show that the spherical optimal measurement area obtained by the aforementioned method is consistent with that obtained experimentally， and can be used to determine the optimal measurement area of other measurement objects， such as points， planes， and so on. The proposed system is demonstrated to be universally applicable and capable of determining the optimal measurement area of machine measurement systems.