Display omitted Carbon dioxide electroreduction (CO2ER) presents a promising strategy for environmentally friendly CO2 utilization due to its low energy consumption. Single-atom nanozymes (SANs), amalgamating the benefits of single-atom catalysts and nanozymes, have become a hot topic in catalysis. Inspired by the intricate structure of cytochrome P450, we designed 81 sandwich-like SANs using Group-VIII transition metals (TMN4-S-TM’N4) and evaluated their performance in CO2ER using density functional theory (DFT). Our investigation revealed that most SANs display superior catalytic activity and improved specific product selectivity in comparison to the Cu (211) surface. Notably, IrN4-S-TMN4 (TM = Co, Rh, Pd) exhibited selective CO2 reduction to CO with remarkable limiting potentials (UL) of −0.11, −0.07, and −0.09 V, respectively, demonstrating potential as artificial CO dehydrogenases. Furthermore, RuN4-S-RuN4 exhibited formate dehydrogenase-like activity, resulting in selective production of HCOOH at a UL of −0.10 V. Machine learning analysis elucidated that the exceptional activity and selectivity of these SANs stemmed from precise modulation of electron density on sulfur atoms, achieved by varying transition metals in the subsurface. Our research not only identifies exceptional SANs for CO2ER but also provides insights into innovative methods for regulating non-bonding interactions and achieving sustainable CO2 conversion.