The box-plate steel structure residence is a box structure with stiffened steel plates directly used as load-bearing walls and floors. In practical engineering, due to the functional requirements of the building, it is necessary to open door or window openings on the box-plate steel structure walls. To study the seismic performance of the box-plate steel structure with openings system, two three-story single-compartment box-plate steel structures with openings modular units were designed and fabricated according to the 1:3 reduced scale. Through the quasi-static loading test, numerical simulation, and theoretical analysis, the failure process, failure mode, lateral force resistant capacity, and hysteresis performance of the specimens were studied. The impact of the different opening areas and opening position on the seismic performance of the box-plate steel structure was emphatically analyzed. The results of the test indicated that the openings on the steel wall plate would reduce the initial stiffness and the lateral force resistant capacity of the specimen; the destruction of the box-plate steel structure with openings modular unit under the low cyclic loading effect started with the tear in the corner of the openings and ended with the tear in the corner steel wall plate. Then, the finite element analysis (FEA) models were developed to supplement the experimental study, and the comparisons were made between measured and simulated results on load versus displacement relationships and failure modes. On the basis of the stressing mechanism of the box-plate structure modular unit, the calculation equation of the lateral force resistant capacity of the box-plate structure with openings modular unit was put forward. Then, the proved finite element analysis (FEA) models were used for parameter analysis of different influence parameters to verify the proposed calculation equation. The results showed that the proposed calculation equation had high accuracy and could be used as a design basis for practical engineering.