Lightweight designs of new-energy vehicles can reduce energy consumption, thereby improving driving mileage. In this study, a lightweight design of a newly developed multi-material electric bus body structure is examined in combination with analytical target cascading (ATC). By proposing an ATC-based two-level optimization strategy, the original lightweight design problem is decomposed into the system level and three subsystem levels. The system-level optimization model is related to mass minimization with all the structural modal frequency constraints, while each subsystem-level optimization model is related to the sub-structural performance objective with sub-structure mass constraints. To enhance the interaction between two-level systems, each subsystem-level objective is reformulated as a penalty-based function coordinated with the system-level objective. To guarantee the accuracy of the model-based analysis, a finite element model is validated through experimental modal test. A sequential quadratic programming algorithm is used to address the defined optimization problem for effective convergence. Compared with the initial design, the total mass is reduced by 49 kg, and the torsional stiffness is increased by 17.5%. In addition, the obtained design is also validated through strength analysis.