The catalytic behavior of transition metals (Sc to Zn) combined in polymeric phthalocyanine (Pc) is investigated systematically by using first-principles calculations. The results indicate that CoPc exhibits the highest catalytic activity for CO oxidation at room temperature with low energy barriers. By exploring the two well-established mechanisms for CO oxidation with O2, namely, the Langmuir–Hinshelwood (LH) and the Eley–Rideal (ER) mechanisms, it is found that the first step of CO oxidation catalyzed by CoPc is the LH mechanism (CO + O2 → CO2 + O) with energy barrier as low as 0.65 eV. The second step proceeds via both ER and LH mechanisms (CO + O → CO2) with small energy barriers of 0.10 and 0.12 eV, respectively. The electronic resonance among Co-3d, CO-2π*, and O2-2π* orbitals is responsible for the high activity of CoPc. These results have significant implications for a novel avenue to fabricate organometallic sheet nanocatalysts for CO oxidation with low cost and high activity.