Sustained mechanical loading on skeletal muscle tissue can lead to degeneration and cell damage over time, resulting in the development of pressure ulcers, particularly in hospital mattresses or for wheelchair-bound users. The primary risk factors for this damage are tissue ischemia caused by pressure in the contact area and tissue compressive strain. In this study, a multi-cell, multi-material foam mattress for the upper comfort layer was developed, with the aim of simultaneously minimizing soft tissue compressive strain and maximum surface pressure on the human buttocks zone. The levels of these factors were estimated using the finite element method (FEM). A multi-objective optimization (MOO) approach was employed, coupling the non-dominated sorting genetic algorithm (NSGA-II) with FEM. This algorithm helped determine the required compressive strength and the optimal cell configurations to achieve the desired outcomes. The majority of the optimal solutions exhibited contact pressures (Cpresss) below the recommended threshold to avoid local tissue ischemia. The optimized cellular material configurations resulted in soft tissue compressive strain of 12% and Cpress of 3.4 kPa, indicating longer safety times for supine support on the foam mattress without the need for repositioning. The optimization process utilized 5 softer foam materials out of the 9 firmness levels tested to achieve these results. The proposed multi-cell, multi-material foam mattress model shows promise for the prevention of pressure sores, as suggested by the optimization findings.