Cuttlebone, the internal skeleton of cuttlefish (Sepia), is a unique natural foam material that has a potential for biomimicry in aviation structural components and in orthopedic implants. It has a cellular ceramic matrix, honeycomb-like, which serves for two main functions: a mechanical rigid shield and buoyancy controlling. The objective of this study is to carry out a comparative research between the cellular cuttlebone structure and the engineering hexagonal honeycomb in terms of an evolutionary advantage and the mechanical properties. Samples of cuttlebones, as-received and artificially broken, were inspected using a low-vacuum scanning electron microscope (LV-SEM). Some small specimens were prepared from the natural skeleton and by 3D printing process. Modeling and simulations using finite element method took place on the both comparative structures in order to analyze the developed stresses during various load conditions. SEM results of the cuttlebone revealed a lamellar matrix (side view) that consists of periodic cells separated by non-continuous, irregular and wavy pillars (top view). A comparative mechanical simulation with the hexagonal honeycomb did not show any advantage of the cuttlebone structure in mechanical loading. Despite these results, the non-continuous pillars, and the open cell walls, are essential for creating the buoyancy control. The liquid hydrostatic pressure inside the cells could break the brittle cell walls in closed hexagonal honeycomb when the complex lamellar structure is loaded. The non-continuous pillars benefit the pressure balancing and prevent the buckling of the cell walls. Therefore, the cuttlebone cellular structure has an evolutionary advantage of stiffness- or strength-to-weight when buckling hydrostatic pressure is an important factor. The lightweight cuttlebone structure might provide a biological inspiration for increasing component toughness in brittle materials engineering.