To investigate the effect of fullerene (C60) and its iron compound (C60-Fe) on the thermal and thermo-oxidative degradation mechanism of high-density polyethylene (HDPE), the Kissinger method, Flynn-Wall-Ozawa method and Coats-Redfern methods are used. The data of thermal and thermo-oxidative degradation are achieved through the thermogravimetric (TG) analysis, and the trapping free-radical ability and the dispersion of C60 or C60-Fe in matrix are characterized by the electron spin resonance (ESR) and transmission electron microscopy (TEM). C60 and C60-Fe improve effectively the thermal and thermo-oxidative stability of HDPE. In N2, C60 and C60-Fe do not change the degradation mechanism of HDPE, and the degradation rate is determined by the random generation and growth of free-radicals. In air, C60 changes the reaction order (n) of HDPE at the oxidation stage and the degradation mechanism at the random fracture. C60-Fe changes the thermo-oxidative mechanism of HDPE due to the formation of cross-linked network.