With projections of increasing drought in the future, understanding how the natural carbon cycle responds to drought events is needed to predict the fate of the land carbon sink and future atmospheric CO2 concentrations and climate. We quantified the impacts of the 2011 and 2012 droughts on terrestrial ecosystem carbon uptake anomalies over the contiguous US (CONUS) relative to non-drought years during 2010–2015 using satellite observations and the carbon monitoring system—flux inversion modeling framework. Soil moisture and temperature anomalies are good predictors of gross primary production anomalies (R2 > 0.6) in summer but less so for net biosphere production (NBP) anomalies, reflecting different respiration responses. We showed that regional responses combine in complicated ways to produce the observed CONUS responses. Because of the compensating effect of the carbon flux anomalies between northern and southern CONUS in 2011 and between spring and summer in 2012, the annual NBP decreased by 0.10 ± 0.16 GtC in 2011, and increased by 0.10 ± 0.16 GtC in 2012 over CONUS, consistent with previous reported results. Over the 2011 and 2012 drought-impacted regions, the reductions in NBP were ~40% of the regional annual fossil fuel emissions, underscoring the importance of quantifying natural carbon flux variability as part of an overall observing strategy. The NBP reductions over the 2011 and 2012 CONUS drought-impacted region were opposite to the global atmospheric CO2 growth rate anomaly, implying that global atmospheric CO2 growth rate is an offsetting effect between enhanced uptake and emission, and enhancing the understanding of regional carbon-cycle climate relationship is necessary to improve the projections of future climate.