Previous studies suggested that the grasslands may be carbon sinks or near equilibrium, and they often shift between carbon sources in drought years and carbon sinks in other years. It is important to understand the responses of net ecosystem production (NEP) to various climatic conditions across the U.S. Great Plains grasslands. Based on 15 grassland flux towers, we developed a piecewise regression model and mapped the grassland NEP at 250 m spatial resolution over the Great Plains from 2000 to 2008. The results showed that the Great Plains was a net sink with an averaged annual NEP of 24 ± 14 g C m−2 yr−1, ranging from a low value of 0.3 g C m−2 yr−1 in 2002 to a high value of 47.7 g C m−2 yr−1 in 2005. The regional averaged NEP for the entire Great Plains grasslands was estimated to be 336 Tg C yr−1 from 2000 to 2008. In the 9 year period including 4 dry years, the annual NEP was very variable in both space and time. It appeared that the carbon gains for the Great Plains were more sensitive to droughts in the west than the east. The droughts in 2000, 2002, 2006, and 2008 resulted in increased carbon losses over drought-affected areas, and the Great Plains grasslands turned into a relatively low sink with NEP values of 15.8, 0.3, 20.1, and 10.2 g C m−2 yr−1 for the 4 years, respectively.