Maize (Zea mays) was grown in indoor chambers with ambient (38 Pa) and elevated (70 Pa) CO2. Drought treatments were imposed 17 days after sowing by withholding nutrient solution. Decreases of soil water content, leaf water potential, net CO2 assimilation and stomatal conductance as a result of drought were delayed approximately 2 days by CO2 enrichment. Concentrations of 28 of 33 leaf metabolites were altered by drought. Soluble carbohydrates, aconitate, shikimate, serine, glycine, proline and eight other amino acids increased, and leaf starch, malate, fumarate, 2-oxoglutarate and seven amino acids decreased with drought. Drought-dependent decreases of nitrate, alanine and aspartate were impacted by limiting nitrogen. Transcript levels of 14 stress-related maize genes responded to drought but this was delayed or modified by CO2 enrichment. Overall, CO2 enrichment eliminated many early responses of maize metabolites and transcripts to water stress but was less effective when drought was severe. Four metabolite groupings were identified by clustering analysis. These groupings included compounds that decreased with water stress, compounds involved in osmotic adjustment and aromatic compounds that alleviate oxidative stress. Metabolite changes also supported the suggestion that water stress inhibited C4 photosynthesis and induced photorespiration.