Low-density polyurethane (PU) foams have been commonly used for some structural purposes in marine applications. However, they have not been exploited as a structural core because of damage tolerance and durability concerns. The major drawbacks of sandwich panels having PU foam core are their poor mechanical properties and vulnerability to marine environmental conditions. Therefore, the present study aimed to contribute to enhancing both the mechanical properties and environmental durability of the traditional PU foam cored-sandwich panels through introducing a potentially suitable alternative. For this purpose, an innovative panel with a multilayered hybrid core consisting of agglomerate cork and PU foam was proposed which was orthogonally stiffened by a thin-walled lattice structure and sandwiched between two composite skins. To characterize the environmental durability and mechanical properties of this novel panel, a wide range of experimental tests including water immersion conditioning, three-point bending, edgewise and flatwise compression, quasi-static indentation, and high-velocity impact perforation were conducted. The sandwich specimens made of composite skins and PU foam core were also manufactured and tested for comparative purposes. Additionally, a nonlinear finite element (FE) analysis was also carried out and the numerical results were compared with the experimental data. The principal findings were that the proposed structural modifications caused a significant enhancement in all the studied mechanical and durability properties of PU foam-cored sandwich panels. It was also found that the FE model could predict load-displacement behavior of the studied sandwich panels under a variety of experimental conditions.