Water samples from a coastal temperate area in the southwest Mediterranean Sea were incubated in 20 l microcosms under full-spectrum solar radiation. We studied the physiological response of phytoplankton to the interacting effects of 3 environmental factors expected to increase due to global change: CO2, nutrient loading and irradiance. Two different levels (High vs. Low) for each factor were combined: CO2 was bubbled at 1000 ppmv CO2 air vs. present atmospheric values, high nutrient treatments had a combination of inorganic and organic nutrients, and light treatments were obtained by covering the tanks with a single or double layer of screen. We measured esterase activity, oxidative stress (ROS), cell death, DNA damage, photosynthetic efficiency and 14C assimilation as particulate or dissolved organic material (POC and DOC respectively). Our results demonstrate that future scenarios of global change showed similar values of primary productivity normalized by chlorophyll as present conditions. The main effect driving phytoplankton physiology was the downregulation of the photosynthetic apparatus by elevated CO2 which affected the whole metabolism. Downregulation decreased the esterase activity, ROS, cell death and DNA damage. Nutrient concentration and light acted as additional modulators, upregulating or contributing to downregulation. The percentage of DO14C extracellular release (PER) was low (0% to 27%) and acted mainly to re-equilibrate the internal balance when cells grown under UVR were exposed to PAR. Re-equilibration by DOC excretion was more necessary in cells acclimated to low CO2, low nutrients and high PAR levels (i.e. “upregulated” cells) and was significantly lower under UVR than under PAR exposures. PER was almost 3 times lower under high CO2 confirming a higher resource use efficiency of phytoplankton under future CO2 concentrations.