A recently developed autonomous benthic lander equipped with an underwater potentiostat and a micromanipulator for in situ voltammetric depth profiling of main redox species in pore waters was deployed for 3 yr at multiple stations along the Satilla River estuary (Georgia, U.S.A.). These measurements revealed that biogeochemical processes in estuarine sediments vary seasonally and are influenced by riverine discharge. A prolonged drought decreased river discharge, altered the salinity gradient in the estuary, and profoundly affected anaerobic respiratory processes in the underlying sediments. Under normal hydrologic conditions, iron reduction was the dominant anaerobic respiratory process across the estuary, likely due to the significant supply of iron from the coastal plane and low salinity of the estuary. Under drought conditions, the salinity of the estuary increased to full seawater strength and carbon remineralization was enhanced significantly. Yet, sulfate reduction was only observed near the mouth of the estuary, whereas a substantial increase in iron reduction was distinctive upriver. Evidence indicates that the increase in iron-reducing activity during the drought resulted mainly from the deposition of mineral particles in the upper estuary when the salinity gradient increased. Altogether, this study demonstrates that the biogeochemical response of estuarine sediments to natural perturbations is rapid and that respiration processes are controlled by a combination of temperature, supply of inorganic and organic substrates, and hydrological processes. These findings also suggest that an increase in the frequency of droughts as a result of climate change may enhance the resiliency of iron-reducing bacteria in river-fed estuarine sediments.