The Northern Great Plains grasslands respond differently under various climatic conditions; however, there have been no detailed studies investigating the interannual variability in carbon exchange across the entire Northern Great Plains grassland ecosystem. We developed a piecewise regression model to integrate flux tower data with remotely sensed data and mapped the 8-d and 500-m net ecosystem exchange (NEE) for the years from 2000 to 2006. We studied the interannual variability of NEE, characterized the interannual NEE difference in climatically different years, and identified the drought impact on NEE. The results showed that NEE was highly variable in space and time across the 7 yr. Specifically, NEE was consistently low (−35 to 32 g C · m⁻² · yr⁻¹) with an average annual NEE of −2 ± 24 g C · m⁻² · yr⁻¹ and a cumulative flux of −15 g C · m⁻². The Northern Great Plains grassland was a weak source for carbon during 2000–2006 because of frequent droughts, which strongly affected the carbon balance, especially in the Western High Plains and Northwestern Great Plains. Comparison of the NEE map with a drought monitor map confirmed a substantial correlation between drought and carbon dynamics. If drought severity or frequency increases in the future, the Northern Great Plains grasslands may become an even greater carbon source.