Based on the M06-2X density functional, the catalytic oxidation of CO by O2 over Mo-embedded graphene was investigated in detail. The model with molybdenum atom embedded in double vacancy (DV) in a graphene sheet was considered. It is found that the complete CO oxidation reactions over Mo-DV-graphene include a two-step process, in which the first step prefers to Langmuir–Hinshelwood mechanism and followed the progress of CO oxidation with a remaining atomic Otop. Compared with the structure of Mo atom decorated at the single carbon vacancy on graphene (Mo-SV-graphene), the catalytic activity of Mo-DV-graphene is weaker. The present results imply that the catalytic activity of Mo-embedded graphene for CO oxidation can be improved by increasing the ratio of single vacancy (SV).