To design highly efficient catalysts for the cleavage of the C–O/C–C bond is the key task in the depolymerization of lignin. Bimetallic alloy catalysts Au–Pd-CTFs were developed to be effective in the oxidative cleavage of β-O-4 lignin model compounds with O2. Au–Pd nanoparticles with an Au/Pd molar ratio between 1 : 1 and 1 : 1.5 showed the highest cleavage efficiency. The kinetics of the reaction process revealed that a synergistic effect between Au and Pd played a crucial role in the oxidation of Cα–OH into CαvO, which was the rate-determining step for the whole oxidative cleavage process. Further insight revealed that the cooperative effect between Au–Pd nanoparticles and the support covalent triazine frameworks (CTFs) facilitated the cleavage of the formed β-O-4 ketone compound to the corresponding aromatics. In addition, Au–Pd-CTF catalysts also showed efficiency in the oxidative transformation of the organosolv lignin. This catalytic system will provide guidance in the oxidative cleavage of β-O-4 linkages in lignin.