The size of the heat exchanger is an important factor determining the dimensions of the cold box in helium cryogenic systems. In this paper, a counter-flow multi-stream plate-fin heat exchanger is optimized by means of a spatial interpolation method coupled with a hybrid genetic algorithm. Compared with empirical correlations, this spatial interpolation algorithm based on a kriging model can be adopted to more precisely predict the Colburn heat transfer factors and Fanning friction factors of offset-strip fins. Moreover, strict computational fluid dynamics simulations can be carried out to predict the heat transfer and friction performance in the absence of reliable experimental data. Within the constraints of heat exchange requirements, maximum allowable pressure drop, existing manufacturing techniques and structural strength, a mathematical model of an optimized design with discrete and continuous variables based on a hybrid genetic algorithm is established in order to minimize the volume. The results show that for the first-stage heat exchanger in the EAST refrigerator, the structural size could be decreased from the original 2.200 × 0.600 × 0.627 (m3) to the optimized 1.854 × 0.420 × 0.340 (m3), with a large reduction in volume. The current work demonstrates that the proposed method could be a useful tool to achieve optimization in an actual engineering project during the practical design process.