Production of valuable chemicals from CO2 is highly desired for the purpose of controlling CO2 emission. Toward that, enzymatic reduction of CO2 for the production of methanol appeared to be especially promising. That has been achieved by reversing the biological metabolic reaction pathways. However, hitherto, there has been little discussion on the thermodynamic feasibility of reversing such biological pathways. The reported yields of methanol have been generally very low under regular reaction conditions preferred by naturally evolved enzymes. The current work examines the sequential enzymatic conversion of CO2 into methanol from a thermodynamic point of view with a focus on factors that control the reaction equilibrium. Our analysis showed that the enzymatic conversion of carbon dioxide is highly sensitive to the pH value of the reaction solution and, by conducting the reactions at low pHs (such as pH 6 or 5) and ionic strength, it is possible to shift the biological methanol metabolic reaction equilibrium constants significantly (by a factor of several orders of magnitude) to favor the synthesis of methanol.