We explore the potential role of atmospheric carbon dioxide (CO2) on isoprene emissions using a global coupled land–atmosphere model [Community Atmospheric Model–Community Land Model (CAM–CLM)] for recent (year 2000, 365 ppm CO2) and future (year 2100, 717 ppm CO2) conditions. We incorporate an empirical model of observed isoprene emissions response to both ambient CO2 concentrations in the long-term growth environment and short-term changes in intercellular CO2 concentrations into the MEGAN biogenic emission model embedded within the CLM. Accounting for CO2 inhibition has little impact on predictions of present-day global isoprene emission (increase from 508 to 523 Tg C yr−1). However, the large increases in future isoprene emissions typically predicted in models, which are due to a projected warmer climate, are entirely offset by including the CO2 effects. Projected global isoprene emissions in 2100 drop from 696 to 479 Tg C yr−1 when this effect is included, maintaining future isoprene sources at levels similar to present day. The isoprene emission response to CO2 is dominated by the long-term growth environment effect, with modulations of 10% or less due to the variability in intercellular CO2 concentration. As a result, perturbations to isoprene emissions associated with changes in ambient CO2 are largely aseasonal, with little diurnal variability. Future isoprene emissions increase by more than a factor of two in 2100 (to 1242 Tg C yr−1) when projected changes in vegetation distribution and leaf area density are included. Changing land cover and the role of nutrient limitation on CO2 fertilization therefore remain the largest source of uncertainty in isoprene emission prediction. Although future projections suggest a compensatory balance between the effects of temperature and CO2 on isoprene emission, the enhancement of isoprene emission due to lower ambient CO2 concentrations did not compensate for the effect of cooler temperatures over the last 400 thousand years of the geologic record (including the Last Glacial Maximum).