The thermal vacuum test (TVT) is an important verification process in the development of spacecraft and load. There are often multiple temperature points on the device under test (DUT) that require control. The interaction among multiple channels poses a challenge for temperature control in the TVT. To solve this problem, a multi-channel Smith proportional–integral–derivative (PID) controller based on a grouping neural network (Grouping-NN) is proposed. Firstly, the mathematical derivation for a typical multi-channel temperature control model of the TVT is carried out. Then, the multi-channel interaction system is identified using a Grouping-NN to predict the output temperature of each channel by grouping the hidden layer neurons according to the number of channels. Finally, two Grouping-NNs are utilized to update the Smith predictor, and the time-delay error is fed back to the PID controller, which is used to optimize the control effect of the multi-channel interaction system under high time delay. The proposal is compared with the traditional PID controller and Smith predictor-based PID controller through simulation. The simulation results show that the proposed method has better suppression of overshooting. In addition, the algorithm is verified by controlling the temperature of six channels in a practical thermal vacuum test.