Interactive effects of CO2 and water availability have been predicted to alter the competitive relationships between C3 and C4 species over geological and contemporary time scales. We tested the effects of drought and CO2 partial pressures (pCO2) ranging from values of the Pleistocene to those predicted for the future on the physiology and growth of model C3 and C4 species. We grew co-occurring Abutilon theophrasti (C3) and Amaranthus retroflexus (C4) in monoculture at 18 (Pleistocene), 27 (preindustrial), 35 (current), and 70 (future) Pa CO2 under conditions of high light and nutrient availability. After 27 days of growth, water was withheld from randomly chosen plants of each species until visible wilting occurred. Under well-watered conditions, low pCO2 that occurred during the Pleistocene was highly limiting to C3 photosynthesis and growth, and C3 plants showed increased photosynthesis and growth with increasing pCO2 between the Pleistocene and future CO2 values. Well-watered C4 plants exhibited increased photosynthesis in response to increasing pCO2, but total mass and leaf area were unaffected by pCO2. In response to drought, C3 plants dropped a large amount of leaf area and maintained relatively high leaf water potential in remaining leaves, whereas C4 plants retained greater leaf area, but at a lower leaf water potential. Furthermore, drought-treated C3 plants grown at 18 Pa CO2 retained relatively greater leaf area than C3 plants grown at higher pCO2 and exhibited a delay in the reduction of stomatal conductance that may have occurred in response to severe carbon limitations. The C4 plants grown at 70 Pa CO2 showed lower relative reductions in net photosynthesis by the end of the drought compared to plants at lower pCO2, indicating that CO2 enrichment may alleviate drought effects in C4 plants. At the Pleistocene pCO2, C3 and C4 plants showed similar relative recovery from drought for leaf area and biomass production, whereas C4 plants showed higher recovery than C3 plants at current and elevated pCO2. Based on these model systems, we conclude that C3 species may not have been at a disadvantage relative to C4 species in response to low CO2 and severe drought during the Pleistocene. Furthermore, C4 species may have an advantage over C3 species in response to increasing atmospheric CO2 and more frequent and severe droughts.