The design optimization of structures under multi-hazard scenarios is challenging, especially when different hazards have contradicting influences on the selection of design parameters. A reliability-based multi-hazard optimization framework for base-isolated buildings is presented here. The multi-hazard optimization framework is proposed to ensure the selection of suitable isolation system design parameters such that predefined reliability-based performance criteria are satisfied under the considered hazards. The moving least squares (MLS)-based response surface methodology (RSM), i.e., MLS-RSM, is implemented for the stochastic evaluation of the response quantities. Also, the weighted composite desirability function is adopted in the framework to satisfy contradicting design objectives under different hazards, wherein multiple performance objectives are considered for each hazard. Moreover, a method of computing the weights of the individual desirability function is derived based on the relative importance of the different hazards and response quantities. The proposed framework is implemented and numerically studied for the reliability-based multi-hazard optimization of multi-story buildings equipped with elastomeric rubber bearings, i.e., lead-core rubber bearing (LCRB) and laminated rubber bearing (LRB). The numerical investigation is conducted considering two multi-hazard scenarios: (a) earthquake ground motion (EQGM) and blast-induced ground motion (BIGM), and (b) EQGM and wind load (WL). The presented results show the suitability and effectiveness of the proposed framework for the multi-hazard optimization of base-isolated buildings considering the contradicting effects of different hazards. Moreover, the effects of the intensities of various hazards in the reliability-based optimization are studied and presented.