<p>Polyurethanes (PUs) are widely used in various industries, but their durability raises significant disposal and environmental concerns. Enzymatic degradation offers a sustainable approach to address these challenges by providing a pathway for PU waste management. This study investigates the enzymatic degradation pathways of PU structures of varying complexity using lipase, protease, peroxidase, and combinations of these enzymes. The focus is on elucidating the mechanisms of degradation and structural changes through structure characterization and thermal analysis techniques. Complementing the experimental analyses, a comprehensive computational study evaluates the interactions between the enzyme and the PU structures. The computational results are then compared with the experimental findings, providing a thorough understanding of these interactions. The findings underscore the potential of enzymatic degradation of PU and the effectiveness of enzyme mixtures, especially the combination of lipase and peroxidase, as well as the synergistic action of all three enzymes. Peroxidase emerges as a highly efficient catalyst for PU degradation, complementing the esterase and amidase enzymes previously studied in this context. The key amino acids that participate in the binding of the enzymes to PUs are also highlighted. This research underscores the promise of enzymatic approaches for environmentally friendly PU recycling.</p>