The effect of perforating the honeycomb walls of a honeycomb sandwich panel on the dynamic bending stiffness and sound transmission loss of the panel is investigated. The dynamic bending stiffness and sound transmission loss of several sandwich panels with different cores are calculated using a semi-analytical method, and the static bending stiffness and flatwise stiffness of these structures are also analyzed with the finite element method. Furthermore, the influences of the honeycomb shape, the hole shape of the perforated honeycomb wall, the number of perforations, and the wall thickness on the vibro-acoustic and mechanical properties of the sandwich panel are investigated. The results show that the static mechanical performance of the sandwich panel quickly reaches a high level when the ratio of honeycomb wall thickness to length t/l is about 5.3 × 10-3 and a square hole in the honeycomb wall can bring superior characteristics of "high static and low dynamic properties," significantly improving the sound insulation of the sandwich panel. This study makes an effective reference for the optimized design of the innovative sandwich structure in practical applications.