A top-down strategy is performed to design Ti3C2O2 MXene-based single atom catalysts (SACs) considering the coordination environment and active metal center. A total of 50 SAC candidates composed of 25 transition metals (TMs) on N, S or N, N co-coordinated Ti3C2O2 (NS/NN-Ti3C2O2) are designed and screened for electrochemical CO2 reduction reaction (CO2RR) to CO. Consequently, 36 TM-NS/NN-Ti3C2O2 structures with considerable stability show stable side-on/end-on CO2 chemisorption, which are then selected for further investigation of CO2RR performance. Analysis on the limiting potential of CO production and the competition with HCOOH production, CO reduction, and hydrogen evolution reaction indicates Ru-NS-Ti3C2O2 and Co-NN-Ti3C2O2 as outstanding catalysts for CO2RR to CO. In actual electrocatalysis, Ru-NS-Ti3C2O2 exhibits an excellent electric field responding effect with ultra-low reaction energies at potentials of −0.80–0 V vs SHE, thus surpassing most of the reported catalysts by far. The two-dimensional descriptor corresponding to the relationship between SACs-intermediate interaction and CO2RR performance, within the near-optimal region of −0.30 < binding energy (Eb(COOH)) < 0.19 eV and −0.30 < Eb(CO) < 0 eV, is demonstrated for rapid screening of candidate catalysts. This work highlights Ti3C2O2 based N, S co-coordination Ru SAC as an outstanding electrocatalyst for CO2RR to CO, and provides a feasible strategy for rational design and screening of CO2RR catalysts.