Foxtail millet (Setaria italica) is a nutrient-rich food source traditionally grown in arid and semi-arid areas, as it is well adapted to drought climate. Yet there is limited information as how the crop responses to the changing climate. In order to investigate the response of foxtail millet to elevated [CO2] and the underlying mechanism, the crop was grown at ambient [CO2] (400 mu mol mol(-1)) and elevated [CO2] (600 mu mol mol(-1)) in an open-top chamber (OTC) experimental facility in North China. The changes in leaf photosynthesis, chlorophyll fluorescence, biomass, yield and global gene expression in response to elevated [CO2] were determined. Despite foxtail millet being a C-4 photosynthetic crop, photosynthetic rates (P-N) and intrinsic water-use efficiency (WUEi), were increased under elevated [CO2]. Similarly, grain yield and above-ground biomass also significantly increased (P < 0.05) for the two years of experimentation under elevated [CO2]. Increases in seeds and tiller number, spike and stem weight were the main contributors to the increased grain yield and biomass. Using transcriptomic analyses, this study further identified some genes which play a role in cell wall reinforcement, shoot initiation, stomatal conductance, carbon fixation, glycolysis / gluconeogenesis responsive to elevated [CO2]. Changes in these genes reduced plant height, increased stem diameters, and promote CO2 fixation. Higher photosynthetic rates at elevated [CO2] demonstrated that foxtail millet was not photosynthetically saturated at elevated [CO2] and its photosynthesis response to elevated [CO2] were analogous to C-3 plants.