To maximize the seismic performance and minimize the material cost of the typical highway reinforced concrete (RC) bridges, a resilience-based multi-objective optimal seismic design method is proposed in this study. The size of elastomeric bearings and the cross-section arrangement of RC piers are chosen as the design parameters. To improve the accuracy and efficiency, the nonlinear time history analysis (NTHA) based cloud analysis approach is associated with the response surface method (RSM) to obtain the seismic resilience during the seismic optimization process. Moreover, the optimization problem is solved through an improved version of non-dominated sorting genetic algorithm (NSGA-II) algorithm. Following, the proposed method is applied to a typical highway RC bridge, and the optimal design schemes are determined from the Pareto optimal solutions. The results show that the resilience response surface model can be used to accurately predict the seismic resilience of bridges. The proposed method can adjust the damage grades of various components by considering the contribution of various components, entailing the minimization of material cost and the maximization of seismic resilience.