The prefabricated reinforced concrete column-steel beam (RCS) frame is an innovative and efficient structural system. To promote the application of the prefabricated RCS frame, a practical seismic design method based on the limit state design was proposed. The elastic method based on the bearing capacity of components was adopted to design frames with different ground motion intensities. When the designed frames are under the strong-column-weak-beam criterion, the capacity and demand values of over-strength factors were calculated, and the over-strength factors were adopted to calculate the yield base shear. Based on the yield base shear and yield mechanism, the semi-rigid connections were designed according to the plastic method, while the beams and columns were designed based on the capacity method. The proposed design method was successfully applied to a six-story prefabricated RCS frame and validated by inelastic analyses. Furthermore, the proposed method can also provide references for other prefabricated frames.