For liquid hydrogen transportation, thermal insulation materials that are lightweight, compact and exhibit high-performance have been pursued for several decades, and variable density multi-layer insulation (VD-MLI) has been regarded as a promising choice. The thermal insulation performance of the insulation materials is important, but is not at the top of the list; many constraints, such as the space and weight of the insulation structures, are imposed on the design of a VD-MLI. Consequently, this makes the optimization of VD-MLIs more complicated. The present authors conducted a multi-objective optimization of a VD-MLI stacked with specific insulation units. The number of repetitions of the basic insulation unit was regarded as the dimensionless design parameter of the VD-MLI. Based on the experimentally validated layer-by-layer (LBL) model for MLI design, the multi-objective optimization of VD-MLI for liquid hydrogen storage was conducted by the combination of proper orthogonal decomposition with a general regression neural network (POD-GRNN) surrogate model optimization framework. The results showed that the optimal solutions for VD-MLI configurations could be achieved under different constraints. The present optimization framework provides a new reference for the optimization of VD-MLI for cryogenic liquid storage.