Coastal landscapes are increasingly exposed to seawater due to sea level rise and extreme weather events. The biogeochemical responses of these vulnerable ecosystems are poorly understood, limiting our ability to predict how their role in global biogeochemical cycles will shift under future conditions. Here we evaluate how antecedent conditions influence the biogeochemical response of soil to seawater inundation events based on a 42-day laboratory incubation experiment with soils collected from a natural salinity gradient across a coastal floodplain. We recorded high-frequency carbon dioxide (CO2) and methane (CH4) gas fluxes from intact soil cores and characterized thermodynamic favorability and molecular features between control and treatment cores inundated with estuarine water collected at high tide. Mean CO2 and CH4 fluxes were higher after inundation compared to the control cores for soils that had low in situ salinity. Soils with low in situ salinity also exhibited significant shifts in organic matter profiles after inundation, with surficial soils (0-7.5 cm) becoming more enriched in phenolic compounds, compared to deeper soils (7.5-15 cm). The number of biochemical transformations, inferred from mass spectrometry, increased significantly after inundation for soils with low in situ salinity, suggesting an increase in microbial activity following inundation. Our results suggest that seawater inundation of low-salinity terrestrial environments can lead to increased microbial activity, preferential depletion of more thermodynamically favorable compounds, and increased soil carbon release. We conclude that the biogeochemical impacts of future seawater exposure will be modulated by antecedent conditions associated with landscape position within coastal watersheds.