ABSTRACTElevated CO2 concentration (eCO2) can modulate the response of crop plants to drought stress (DS). This study aimed to investigate the response of leaf gas exchange, chlorophyll fluorescence, antioxidant activities, osmotic adjustment substance, phytohormone and signal transduction regulatory enzymes, as well as related genes in foxtail millet to DS (water stress for 10 days), ambient condition (aCO2, 400 μmol mol−1) and eCO2 (600 μmol mol−1). eCO2 significantly increased the net photosynthetic rate, maximum net photosynthetic rate, chlorophyll a content, transpiration rate and stomatal conductance, but did not affect leaf instantaneous water‐use efficiency under DS. eCO2 also significantly enhanced the quantum yield of Photosystem II (PSII), photosynthetic electron transport, and proportion of open PSII reaction centers under DS. Moreover, eCO2 significantly increased abscisic acid (ABA) content, proline content, and the activities of peroxidase, superoxide dismutase, and calcium‐dependent protein kinase under DS, leading to a significant reduction in malondialdehyde content. eCO2 significantly increased the expressions of gene encoding ABA‐, stress‐ and ripening‐induced proteins and ABA‐responsive element binding factor under DS. Our results clearly demonstrated the vital role of eCO2 in mitigating the drought‐induced damage over ambient CO2 grown foxtail millet.