In recent years, significant advances in materials science and engineering have enabled the development and application of novel materials in engineered structures. Among these materials, composites have attracted increasing attention due to their high strength-to-weight ratio, favorable mechanical properties, and design flexibility. One important application of these materials is the fabrication of sandwich panels with lightweight cores and stiff skins, which can serve as suitable alternatives to conventional materials in sectors such as construction and transportation. In the present study, the fabrication and mechanical characterization of bio-based wood-core composite sandwich panels were investigated. Thermoplastic samples were fabricated using the hot-press method, while thermoset samples were produced by the vacuum-assisted resin infusion process. The face sheets of the thermoplastic panels consisted of glass fiber–reinforced polyamide 6, whereas glass fiber–reinforced epoxy resin was used as the face sheet in thermoset samples. Mechanical performance was assessed by three-point bending tests, and parameters such as face bending stress, core bending stress, and overall flexural strength were obtained experimentally. Furthermore, indices of strength-to-weight ratio and energy absorption were calculated and compared across the different systems. Finally, the results were benchmarked against findings from previous studies to highlight performance improvements and potential advantages of the proposed configurations.