The performance of a Sr₂Fe_1.5Mo_0.5O_6−δ (SFMO) perovskite anode has been investigated under solid oxide fuel cell conditions while operating on CO and syngas fuels using periodic density functional theory and microkinetic modeling. Three surface models with different Fe/Mo ratios and oxygen vacancies on the gas exposed surface layer are used to identify the active site and electro-oxidation mechanism for CO and a mixture of CO and H₂. Calculated current densities suggest that SFMO anodes exhibit lower performance while operating on CO compared to H₂ fuel and a surface with a higher Mo concentration in the top most layer exhibits a higher activity for both fuels. Furthermore, the model predicts that desorption of CO₂ and formation of an oxygen vacancy, which is found to be the charge transfer step, is rate-controlling for CO electro-oxidation at operating voltage. The CO oxidation activity can thus be improved by increasing the Mo content or by adding small amounts of an active transition metal on the surface that facilitates the oxygen vacancy formation process by delocalizing the electrons at the vacant site. In the presence of a mixture of CO, H₂ and H₂O gas, the water–gas shift reaction (CO + H₂O ⇌ CO₂ + H₂) is rapid at operating voltage and H₂ electro-oxidation contributes mostly to the overall observed electrochemical activity, while CO is primarily chemically oxidized to CO₂. A higher Mo content in the SFMO surface promotes again a higher activity for syngas fuels with high CO content.