Coated microbubbles have become important ultrasound contrast agents because of their nonlinear oscillatory behavior, particularly their ability to generate subharmonic signals. These signals can improve the contrast-to-tissue ratio and enhance imaging quality through deeper penetration and lower attenuation. However, the strength of the subharmonic response is highly dependent on several parameters, including the initial bubble radius, excitation frequency, and acoustic pressure amplitude. Inappropriate parameter selection may reduce signal quality or even lead to microbubble destruction. In this study, a genetic algorithm was used as a metaheuristic optimization method to determine the optimal excitation conditions for maximizing subharmonic response intensity. The dynamic behavior of coated microbubbles was modeled using the modified Rayleigh-Plesset equation combined with the Marmottant shell model. The optimization objective was defined as the maximization of subharmonic scattering power by varying key parameters such as initial radius, excitation frequency, and pressure amplitude. The results showed that optimal performance was achieved for initial radii of 3–4 μm, excitation frequencies around 2 MHz, and pressure amplitudes between 1500 and 1800 kPa. Moreover, simultaneous multi-parameter optimization proved more efficient than single-parameter optimization, enabling more stable and effective operating conditions for enhanced ultrasound imaging.