Abstract: In this study, the thermal degradation mechanism of avermectin (AVM) was analyzed via experiments and density functional theory calculations (DFT). The experimental results of AVMD pyrolysis indicated that the removal rate of AVM residues reached peak value of 99.88% above 250 °C. The main product of AVM pyrolysis was alcohols. Based on the C−O bonds breaking, four potential degradation pathways were proposed. The findings of the calculations were in agreement with those of the experiments. These results provide theoretical and empirical guidance for the development of safe antibiotic disposal technology.