Plant layout design is a complex task requiring a wealth of engineering experience. A well-designed layout can extraordinarily reduce various costs, so layout study is of great value. To promote the research depth, plenty of considerations have been taken. However, an actual plant may have several frames and how to distribute facilities and determine the location of them in the different frames has not been well studied. In this work, frames are set as a special kind of inner structure and are added into the model to assign facilities into several blocks. A quantitative method for assigning facilities is proposed to let the number of cross-frame connections be minimized. After allocating the facilities into several blocks, each frame is optimized to obtain initial frame results. With designer decisions and cross-frame flow information, the relative locations of frames are determined and then the internal frame layouts are optimized again to reach the coupling optimization between frame and plant layout. Minimizing the total cost involving investment and operating costs is set to be the objective. In the case study, a plant with 138 facilities and 247 material connections is studied. All the facilities are assigned into four frames, and only 17 connections are left to be cross-frame ones. Through the two optimizations of each frame, the length of cross-frame connections reduces by 582.7 m, and the total cost decreases by 4.7 × 105 ¥/a. Through these steps, the idea of frame is successfully applied and the effectiveness of the proposed methodology is proved.