Polyurethane foams are widely used in applications requiring efficient energy absorption and damping, especially in components subjected to repeated mechanical loading. This study investigates the cyclic compressive behavior of an anisotropic polyurethane foam to understand how its mechanical response evolves under successive loading cycles. Microscale analysis was first conducted to characterize the foam’s directional properties, revealing a cellular microstructure with a predominant orientation that underpins its anisotropic behavior. The foam was then subjected to cyclic compression along different principal directions to evaluate the influence of loading orientation on mechanical performance. Experimental results indicate a progressive decline in stiffness and overall mechanical response with increasing cycles, demonstrating pronounced cyclic softening. Furthermore, the degree of softening is strongly dependent on the direction of applied load, highlighting the significant role of anisotropy in governing the foam’s behavior under repeated deformation. These findings provide insights into the directional evolution of mechanical properties under cyclic loading with direct implications for their application in energy-dissipating systems.