Pigweed is an increasingly aggressive weed in semiarid environments such as Mediterranean areas, and in general the control of all Amaranthus species is becoming more and more difficult. Increasing pigweed aggressiveness could be a result of its ability to keep a high water use efficiency under drought conditions. An experiment was conducted to study the effect of water stress on the photosynthetic capacity, growth, and leaf water potential of pigweed at the field level and assess if this species, as a model for C4 weeds, is CO2-saturated at the current level of atmospheric CO2 in a Mediterranean area. Pigweed was studied within a naturally occurring weed population in a bell pepper field in southern Italy where a rain-fed treatment (V0) was compared to a fully irrigated one (V100) corresponding to the restoration of 100% of the maximum crop water evapotranspiration. Soil water content was measured periodically, and net assimilation rate, stomatal conductance, transpiration rate, and intercellular CO2 concentration were determined on pigweed leaves. Photosynthetic rates of 37.6 µmol m−2 s−1 in V100 and 13.9 µmol m−2 s−1 in V0 were recorded, with higher transpiration rates in V100; consequently stomatal conductance was significantly lower in rain-fed conditions (0.08 mol m−2 s−1)) compared to the irrigated treatment (0.30 mol m−2 s−1). Photosynthesis in pigweed is not completely CO2-saturated at the current atmospheric CO2 level in the Mediterranean area and this could affect competition and increase of aggressiveness toward crops at the actual CO2 atmospheric concentration in agro-ecosystems. This occurs because unlike other C4 crops already saturated for CO2, weeds that are not CO2-saturated will remain CO2-sensitive to higher ambient CO2 levels. Thus, when they are grown in mixed stands where competition occurs, they can still suppress the slower-growing species.