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Polyethylene is a widely used plastic that presents challenges in degrading within natural environments. Therefore, the degradation of polyethylene is of utmost importance. Currently, physical or chemical methods are efficient but more dangerous. Conversely, biological methods are safer but less efficient. Combining the two approaches to create entirely new polyethylene degradation pathways is a viable idea. Based on the previous research, it is an effective method to add ester bonds inside polyethylene and degrade using cutinase or lipase. However, the method only detected a decrease in molecular weight and did not observe a rate of weight loss at the macroscopic level. In this research, rapid degradation of polyethylene is achieved by optimizing catalysis conditions and machine learning. Finally, the maximum weight loss up to 80.51% within 24h and a mild catalysis environment (60-80°C). Furthermore, the method’s versatility was confirmed for cutinase and lipase. Overall, this research has established an effective, efficient, and mild degradation process of polyethylene, significantly contributing to the progress in polyethylene degradation.