Through the introduction of multi-frequency sonication in High Intensity Focused Ultrasound (HIFU), efficiency enhancement has been noted in several applications including thrombolysis, tissue ablation, sonochemistry, and sonoluminescence. Researchers reported theoretically and experimentally that the enhanced effect is due to the enhancement of inertial cavitation. One key experimental observation is that multi-frequency ultrasound can help lower the inertial cavitation threshold, thereby improving the power efficiency. However, this has not been theoretically corroborated. Numerical simulation is an important tool for understanding cavitation as well as for optimization purposes. For these reasons, a numerical investigation on the inertial cavitation threshold of microbubbles under multi-frequency ultrasound irradiation was conducted.