Environmental accumulation of polyamide (nylon) waste is a pressing global issue. Microbial enzyme-mediated biodegradation serves as the most attractive and eco-friendly approach for the sustainable management of end-of-life nylons. However, it is hampered by inefficient degradation rates and a limited knowledge of potential enzymes and mechanisms. Given its significance, this review aims to provide a comprehensive overview of the advancements in enzymatic nylon depolymerization, their mechanisms, their challenges, and their opportunities. The review can then inform protein engineering and enhance the discovery of novel nylon-degrading enzymes.