<p>This paper presents an innovative scheme for layout optimization of bi-material structures, which can be effectively applied to the design of the structural–acoustic coupled systems subjected to mid-frequency excitation. The basic theory of the scheme is the statistical modal energy distribution analysis (SmEdA). As an improved and extended version from statistical energy analysis (SEA), the core concept of computing energy transfer at the per-mode level enables the SmEdA to address mid-frequency vibration problems. The proposed optimization model aims at minimizing the acoustic energy in the cavity through rational bi-material distribution (stiffer material and softer material), subject to a weight constraint on the stiffer material. The virtual density of the structural plate, obtained by the solid isotropic material with penalization (SIMP) method within the bi-material interpolation model, serves as the design variable. A volume-preserving Heaviside penalization is incorporated into the optimization framework for eliminating the intermediate density region. Moreover, sensitivity analysis is conducted using the complex variable method (CVM) to enhance the computational accuracy and practical applicability of the established optimization framework. Finally, numerical cases are presented to elaborate the practicality of the developed optimization scheme. It can be concluded that: (a) A considerable reduction of the overall acoustic energy within the cavity is observed; (b) the peak value of modal coupling strength is effectively reduced and the corresponding distribution tends toward more homogenization.</p>