The substituted groups in lignin can influence the pyrolysis characteristics. Density functional theory (DFT) was employed to calculate the bond dissociation energies (BDEs) of the Cβ—O bonds in 18 lignin model compounds with β—O—4 linkages. The model compounds were grouped and compared to discuss the effects of hydroxyl and methoxyl groups at different positions on the BDEs. The interactions between different groups were also studied. The results indicated that there was minor influence of the hydroxyl group at Cα. The hydroxyl group at Cγ hardly affected the BDE when there was no methoxyl group at R3. However, when there was methoxyl group at R3, hydrogen bond would be formed between the hydroxyl group at Cγ and the methoxyl group at R2, and thus the spatial structure of the model compound would be strengthened and the BDE was increased. The methoxyl groups at R3 and R4 can reduce the BDEs. The methoxyl group at R3 can obviously reduce the BDEs when there was no hydroxyl group at Cγ. However, the reducing effect was weakened when there was hydroxyl group at Cγ, because the hydrogen bond between the methoxyl group at R3 and hydroxyl group at Cγ would strengthen the ether bond. The methoxyl group at R4 was not influenced by the hydroxyl group at Cγ, and thus the reducing effect on the BDE was stable. The methoxyl group at R1 and R2 had minor effects on the BDE, and moreover, it did not participate in the interactions with other functional groups.