The steel plate shear wall system has been used in a number of buildings as an innovative lateral force resistance system. Stiffened steel plate shear walls possess greater stability and energy absorption during dynamic loading, such as during seismic loading, when compared with unstiffened steel plate shear walls. Openings, however, often exist in the steel plate shear walls due to various functional requirements of the structure. These openings may negatively impact the overall capacity of the shear wall, necessitating additional stiffening. Therefore, an experimental research program was instituted to investigate the seismic behavior of stiffened steel plate shear walls, with and without openings. Strength, stiffness, ductility and energy absorption were evaluated based on the results of reversed cyclic loading tests on three specimens. Two of the test walls had openings, while one wall was constructed without any openings. The test program results showed that stiffened steel plate shear walls exhibit satisfactory seismic behavior, and, as expected, the strength and stiffness characteristics of the walls were reduced in walls with openings. In addition to the test program, an analytical study utilizing a beam–shell mixed Finite Element (FE) model of a single-story wall panel with boundary columns is made to determine the critical factors influencing the shear strength reduction of stiffened wall panels with the opening. Furthermore, extensive numerical calculation and parametric analysis are conducted to derive a simplified formula for the determination of the shear strength reduction coefficient. In addition, complex elasto–plastic FE models of the three specimens are developed to investigate in detail the lateral force resistance behavior of stiffened steel plate shear walls. Good agreement is observed between the experimental and numerical results. Finally, a design method for calculating the lateral resistance capacity, based on the test program and the FE model analysis, is recommended to be used for the routine design practice of stiffened steel plate shear walls.