While (bio)degradation of polymers is a recognized challenge, the influence of additives on this process remains poorly understood. Their presence in commercial polyethylene (PE) may inhibit the degradation process or complicate the recycling. This study aims to develop an enzymatic degradation process for post-consumer high-density polyethylene (HDPE). The HDPE degradation was performed using laccase from Trametes versicolor under mild conditions of temperature and pressure. The process was developed by exploring three key conditions: (i) the biocatalytic medium; (ii) the enzymatic mediator, and (iii) the influence of the presence of additives in the polymers. The most successful enzymatic degradation system involved HDPE from which additives were removed, with a buffer used as the reaction medium and 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) employed as the enzymatic mediator. This system led to a substantial 33% weight reduction of the polymer (versus 3% for HDPE with additive under the same conditions). The characterization of the degraded polymer revealed new bands in the Fourier transform infrared spectroscopy (FTIR) spectra, including a new carbonyl band. In addition, it also showed an increased crystallinity when compared to HDPE with additive under the same conditions. These results suggest that the enzymatic degradation of HDPE occurs through an oxidation process, with the enzyme preferentially attacking the amorphous region of the polymer.