Microbial reduction of arsenic-bearing iron oxides in the deltas of South and Southeast Asia produces widespread arsenic-contaminated groundwater. Organic carbon is abundant both at the surface and within aquifers, but the source of organic carbon used by microbes in the reduction and release of arsenic has been debated, as has the wetland type and sedimentary depth where release occurs. Here we present data from fresh-sediment incubations, in situ model sediment incubations and a controlled field experiment with manipulated wetland hydrology and organic carbon inputs. We find that in the minimally disturbed Mekong Delta, arsenic release is limited to near-surface sediments of permanently saturated wetlands where both organic carbon and arsenic-bearing solids are sufficiently reactive for microbial oxidation of organic carbon and reduction of arsenic-bearing iron oxides. In contrast, within the deeper aquifer or seasonally saturated sediments, reductive dissolution of iron oxides is observed only when either more reactive exogenous forms of iron oxides or organic carbon are added, revealing a potential thermodynamic restriction to microbial metabolism. We conclude that microbial arsenic release is limited by the reactivity of arsenic-bearing iron oxides with respect to native organic carbon, but equally limited by organic carbon reactivity with respect to the native arsenic-bearing iron oxides.