Anthropogenic and environmental pressures on wetland hydrology may trigger changes in carbon (C) cycling, potentially exposing vast amounts of soil C to rapid decomposition. We measured soil CO2 efflux (Rs) continuously from 2009 to 2010 in a lower coastal plain forested wetland in North Carolina, U.S., to characterize its main environmental drivers. To understand and quantify the spatial variation due to microtopography and associated differences in hydrology, measurements were conducted at three microsites along a microtopographic gradient. The seasonal hysteresis in Rs differed by microtopographic location and was caused by the transitions between flooded and nonflooded conditions. Because flooded Rs was small, we reported Rsdynamics mainly during nonflooded periods. A nested model, modified from conventional Q10(temperature sensitivity) model with dynamic parameters, provided a significantly better simulation on the observed variation of Rs. The model performed better with daily data, indicating that soil temperature (Ts) and water table depth (WTD) were the primary drivers for seasonal variation. The diel variation of Rs was high and independent of Ts and WTD, which both had small diel variations, suggesting the likely association with plant activity. Overall, the site-average soil CO2 efflux was approximately 960–1103 g C m−2 yr−1 in 2010, of which 93% was released during nonflooded periods. Our study indicates that Rs is highly linked to hydroperiod and microtopography in forested wetlands and droughts in wetlands will accelerate soil C loss.