Abstract: Spherical open-cell aluminum foam exhibits significant application potential in both vibration damping and energy absorption due to its controllable structure and to its excellent comprehensive properties. However, the dependence of its mechanical properties on its thickness remains unclear. This study investigates the compressive response of spherical-pore aluminum foam at different thicknesses (35 mm, 50 mm, and 65 mm) through quasi-static compression tests combined with finite element simulation. A microscopic representative volume element (RVE) modeling approach based on a “spherical-intersecting-layered” structure formed by stacked spheres is proposed, enabling parametric control of pore size and of porosity while significantly enhancing geometric fidelity. The research results indicate that as the thickness increases, spherical-celled aluminum foam exhibits out-of-plane local instability during compressive failure, with a significantly extended strain range in the plastic plateau stage. Although both energy absorption and specific energy absorption decrease with the increase of the thickness, the energy absorption efficiency gradually increases, reflecting a smoother and more efficient energy dissipation process per unit strain. At a constant thickness, increased porosity reduces the structural load-bearing capacity but results in a smoother compression behavior and delayed densification, further enhancing energy absorption efficiency. Experimental and simulation results show a good consistency in compression response and in energy absorption efficiency, indicating that the “spherical overlapping layer” modeling method proposed can effectively predict the macroscopic mechanical behavior of spherical-pore aluminum foam, and possesses practical applicability.