Most existing hybrid test methods for building structures only consider the horizontal earthquake excitation. For further application, a hybrid test method of multi-story reinforced concrete (RC) frames under the combined excitation of horizontal and vertical earthquakes was developed. In this method, the frame structure calculation model and substructure boundary conditions were reasonably simplified. The horizontal and vertical vibrations of frame structure were simulated by series mass system model and series-parallel multi-mass system model respectively. Then, a complete set of hybrid test program was developed based on the proposed method. In the program, Matlab was adopted to form a motion equation solving module, OpenSees was used to simulate the numerical substructure, and loading equipment HNU-MUST was combined to develop a hybrid test control program. For verifying the proposed method and program, a full-scale RC frame column was designed and fabricated as the test substructure, and a seven-story three-bay RC frame was used as the overall structure for hybrid test. The smooth progress of the test and the stable test control effect verified the feasibility and effectiveness of the method. Test results show that the axial force of the RC frame column varied drastically under the combined excitation of horizontal and vertical earthquakes. The variation of axial force made the force and failure morphology of the specimen more complicated, and could reduce the strength and ductility of the specimen, which eventually resulted in an asymmetry and a certain “pinch” effect of hysteresis curve.