The thermal degradation performance of the polylactic acid (PLA)-based polyurethane resin was investigated by thermogravimetric analysis (TGA), thermogravimetric analysis combined with Fourier transform infrared spectroscopy (TG-FTIR) and thermal cracking gas chromatography/mass spectrometry (PY-GC/MS), while the thermal decomposition mechanism and activation energy were analyzed by different degradation mechanism models. The result demonstrates that the PLA-based polyurethane resin conforms to A2 (nuclear growth) mechanism, and the activation energy of the reaction gradually decreases as the conversion rates increases. The main degradation of polyurethane resin is the decomposition of carbamate, ester group, amide and urea group by comparing the results of the data, and the products of the thermal decomposition are mainly small molecules of primary amine, carbon dioxide, enol, enolic acid and aldehydes.