The isomerization of o-xylene, a prototypical example of shape-selective catalysis by zeolites, was investigated on hierarchical porous ZSM-5. Extensive intracrystalline mesoporosity in ZSM-5 was introduced by controlled silicon leaching with NaOH. In addition to the development of secondary porosity, the treatment also induced substantial aluminum redistribution, increasing the density of Lewis acid sites located at the external surface of the crystals. However, the strength of the remaining Brønsted sites was not changed. The mesoporous zeolite displayed a higher o-xylene conversion than its parent, owing to the reduced diffusion limitations. However, the selectivity to p-xylene decreased, and fast deactivation due to coking occurred. This is mainly due to the deleterious effect of acidity at the substantially increased external surface and near the pore mouths. A consecutive mild HCl washing of the hierarchical zeolite proved effective to increase the p-xylene selectivity and reduce the deactivation rate. The HCl-washed hierarchical ZSM-5 displayed an approximately twofold increase in p-xylene yield compared to the purely microporous zeolite. The reaction was followed by operando infrared spectroscopy to simultaneously monitor the catalytic performance and the buildup of carbonaceous deposits on the surface. Our results show that the interplay between activity, selectivity, and stability in modified zeolites can be optimized by relatively simple post-synthesis treatments, such as base leaching (introduction of mesoporosity) and acid washing (surface acidity modification).