The purpose of the present study is the estimation of the environmental degradation process of oxo-biodegradable polyethylene bags. The degradation process of polyethylene samples, with the addition of a d2w prodegradant, was studied under natural weathering, freshwater (pond), and water in laboratory condition for a period of 48 months. The impact of characteristic parameters of environments on the extent of degradation, monitored by weight changes, mechanical properties, and surface morphology, has been discussed. The degraded polymer samples were also analyzed by FTIR spectroscopy. It was established that the oxo-biodegradable polyethylene samples were hardly prone to degradation in natural freshwater, but more vulnerable to environmental weathering. Abiotic parameters (oxygen, temperature, solar radiation) played a more important role in the degradation process of oxo-biodegradable polyethylene than biotic parameters (microorganisms). Natural weathering led to first fragmentation of the polymeric samples after 18 months, weight loss to 81.6% after 39 months, and complete assimilation after 45 months. In the pond, 48 months incubation resulted in an increase in the weight of the samples (+19%) and a decrease in mechanical properties: tensile strength from 26.31 to 17.35 MPa and elongation at break from 304 to 31%. The biofilm formed on the polymer surface made it difficult for oxygen to reach the degraded material, so oxydegradation in the pond was slower. ATR-FTIR analysis and microscopic observations confirm the degradation taking place in natural environments. No visible degradation changes were observed in the oxo-biodegradable polyethylene after incubation under laboratory water, because of the lack of microorganisms and solar radiation. The degradation of oxo-biodegradable polyethylene in natural environments required a longer incubation time compared to the degradation time declared by the manufacturer.