This study focuses on sound transmission frequency response through honeycomb core sandwich panels with in-plane orientation. Specifically, an optimization technique has been presented to determine the honeycomb unit cell geometric parameters that maximize the sound transmission loss (STL) through a sandwich panel, while maintaining constraints of constant mass and overall dimensions of panel length and height. The vibration characteristics and STL response of a sandwich panel are parameterized in terms of four honeycomb unit cell independent geometric parameters; two side lengths, cell wall thickness, and interior cell wall angle. With constraints of constant mass and overall dimensions, relationships are determined such that the number of independent variables needed to define the honeycomb cell and panel geometry is reduced to three; the integer number of unit cells in the longitudinal direction of the core, number of unit cells in the height direction, and interior cell wall angle. The optimization procedure is implemented by linking a structural acoustic finite-element (FE) model of the panel, with modefrontier, a general purpose optimization software. Optimum designs are obtained in representative frequency ranges within the resonance region of the STL response. Optimized honeycomb geometric solutions show at least 20% increase in STL response compared to standard hexagonal honeycomb core panels. It is found that the STL response is not only affected by the cell wall angle, but strongly depends also on the number of unit cells in the horizontal and vertical direction.