Microbial sulfate reduction occurs ubiquitously in natural environments. In oil and gas reservoirs, the generation of sulfide (also known as souring) can result in the corrosion of steel infrastructure and downgrading of oil quality, among other environmental and health-related concerns. The complex interplay between hydrological, geochemical, and biological processes during souring is poorly understood, preventing effective treatment and mitigation especially in naturally heterogeneous subsurfaces. In this work, three-dimensional flow tank experiments are utilized as a mesoscale experiment that links well-constrained batch and column experiments to field measurements. The mesoscale tank experiment investigating perchlorate treatment of souring is coupled with reactive transport modeling to understand the effects of heterogeneity on souring and effectiveness of perchlorate treatment. Tracer experiments were conducted at the start and end of the experiment to constrain flow pathways and heterogeneities. Isotopic, geochemical, and microbial data revealed that perchlorate effectively inhibited sulfidogenesis and the growth of dominant sulfate reducing Desulfobacteraceae. Perchlorate treatment enriched Desulfobulbaceae, a sulfur-oxidizing group of bacteria, and Sulfurimonas, a potential perchlorate reducer. More organisms, including sulfate reducing bacteria, were observed closer to the influent. Results from the three-dimensional reactive transport model indicate horizontal preferential flows, as a result of the permeability contrast, led to faster bacteria growth (sulfate reducing bacteria) and sulfate reduction in fast flow regions. This work highlights the control that spatial distributions of hydrologic characteristics exert over reservoir souring and treatment.