Abstract Mediated microbial electrosynthesis (MES) represents a promising strategy for the capture and conversion of CO 2 into carbon‐based products. We describe the development and application of a comprehensive multiphysics model to analyze a formate‐mediated MES reactor. The model shows that this system can achieve a biomass productivity of ∼1.7 g L −1 h −1 but is limited by a competitive trade‐off between O 2 gas/liquid mass transfer and CO 2 transport to the cathode. Synthetic metabolic strategies are evaluated for formatotrophic growth, which can enable an energy efficiency of ∼21 %, a 30 % improvement over the Calvin cycle. However, carbon utilization efficiency is only ∼10 % in the best cases due to a futile CO 2 cycle, so gas recycling will be necessary for greater efficiency. Finally, separating electrochemical and microbial processes into separate reactors enables a higher biomass productivity of ∼2.4 g L −1 h −1 . The mediated MES model and analysis presented here can guide process design for conversion of CO 2 into renewable chemical feedstocks.