Cuttlefish, a unique group of marine mollusks, produces an internal biomineralized shell, known as cuttlebone, which is an ultra-lightweight cellular structure (porosity, ∼93 vol%) used as the animal’s hard buoyancy tank. Although cuttlebone is primarily composed of a brittle mineral, aragonite, the structure is highly damage tolerant and can withstand water pressure of about 20 atmospheres (atm) for the species Sepia officinalis. Currently, our knowledge on the structural origins for cuttlebone’s remarkable mechanical performance is limited. Combining quantitative three-dimensional (3D) structural characterization, four-dimensional (4D) mechanical analysis, digital image correlation, and parametric simulations, here we reveal that the characteristic chambered “wall–septa” microstructure of cuttlebone, drastically distinct from other natural or engineering cellular solids, allows for simultaneous high specific stiffness (8.4 MN⋅m/kg) and energy absorption (4.4 kJ/kg) upon loading. We demonstrate that the vertical walls in the chambered cuttlebone microstructure have evolved an optimal waviness gradient, which leads to compression-dominant deformation and asymmetric wall fracture, accomplishing both high stiffness and high energy absorption. Moreover, the distribution of walls is found to reduce stress concentrations within the horizontal septa, facilitating a larger chamber crushing stress and a more significant densification. The design strategies revealed here can provide important lessons for the development of low-density, stiff, and damage-tolerant cellular ceramics. Significance Cellular solids, or foams, are an important class of structural materials for packaging, transportation, and infrastructure due to their mechanical efficiency. Current foams are primarily made of metallic or polymeric materials, while ceramics could potentially serve this goal better, as they have higher specific stiffness and strength, and are chemically more stable. What limits the application of ceramic cellular solids as structural components are their brittleness and flaw sensitivity. Overcoming the fragile nature of ceramic foams, making them lighter while reaching higher stiffness, strength, and energy absorption is challenging but critical toward many applications. In this study, we elucidate how cuttlebone overcomes its intrinsic brittleness through the “wall–septa” microstructure, which could inspire the development of lightweight ceramic cellular solids.