Ultra-pure hydrogen is very much required for a healthy operation of proton exchange membrane (PEM) fuel cells. The concentration of sulfur in the fuel is an important controlling factor because it leads to pollution via sulfur oxides. H2S sorbent or catalysts coated on the particles that are in the order of 100 μm diameters entrapped into a high void volume carrier structure of sintered microfibers are observed to possess significantly higher heterogeneous reaction rates than packed beds of the small particle size. Fundamental reasons for this difference are investigated in this study to determine if such differences are caused by: (1) bed channeling, (2) microscale interstitial/interparticle velocity distributions, and/or (3) effect of presence of fibers. Since microscale fluid effects are not accounted for in traditional reaction engineering formulations, more rigorous approaches to the fluid flow, gaseous diffusion and surface reaction behaviors for a ZnO-based H2S sorbent have been undertaken using computational fluid dynamics (CFD). Simulation results have been compared with carefully prepared experimental samples of microfibrous materials. The experiments involved 14 wt.% ZnO/SiO2 at an operating temperature of 400 °C and a challenge gas consisting of 0.5 vol. % of H2S in H2 and were used to validate the CFD models (both geometric and species transport). These results show that CFD predictions of chemical conversion of H2S are within 10–15% of the experimentally measured values. The effects of residence time and dilution with void on the chemical conversion have been studied. Different microfibrous materials were modeled to study the effect of fiber diameter and fiber loading on the chemical conversion and pressure drop. It is observed that the dilution with void has a negative effect on the conversion; however, the addition of fibers not only compensated for the negative effect of dilution but also increased the reaction rate. The main goal of this study is to use CFD as a tool to design new materials with enhanced reactivity and reduced pressure drop. Our work suggests that new materials with enhanced chemical reactivity for a given pressure drop should be designed with fewer, larger diameter fibers. Our results show that the logs of reduction of H2S per pressure drop increased by a factor of six for the material with 8 μm diameter fibers with 3% volume fraction relative to a packed bed with same catalyst loading.