A novel hydrogeochemical modeling approach is developed to unravel thermochemical sulfate reduction (TSR) in hydrocarbon reservoirs. Our numerical model couples a web of interconnected hydrogeochemical reactions to three-dimensional (3-D) and reservoir-wide diffusive mass transport. Our modeling approach simulates a semigeneric gas reservoir sealed by anhydrite. The calculated diagenetic processes fit the observations in reservoirs affected by TSR: formation of water, precipitation of calcite, metal (di-)sulfides, and elemental sulfur as replacements of dissolved anhydrite at the expense of CH4(g), as well as formation of hydrogen sulfide (H2S). By varying input parameters, the crucial factors controlling TSR have been identified. Our results highlight that reservoir-wide diffusive mass transport is one prerequisite for TSR. An increase in the rate constant of abiotic sulfate reduction (ASR) and in diffusive mass fluxes, as well as lack of precursor minerals for metal (di-)sulfide precipitation, can increase the souring intensity and accelerate H2S outgassing. In contrast, precipitation of elemental sulfur, which is stable according to the chemical thermodynamics, weakens H2S formation. Our modeling shows that TSR is complex and cannot be represented by the single reaction ASR and by simple correlations between the rate constant of ASR and the H2S gas content. The application of 3-D reactive transport modeling presented here, despite its semi generic nature, provides a good example of how such an approach can be used ahead of drilling. Our modeling helps to investigate TSR in time and space to quantify the mass conversion of all reactants involved within this web and to predict the souring level.