We investigated the impact of crystallographic orientation on the photocatalytic activity of single crystalline WO3 thin films prepared by molecular beam epitaxy on the photodegradation of rhodamine B (RhB). A clear effect is observed, with (111) being the most reactive surface, followed by (110) and (001). Photoreactivity is directly correlated with the surface free energy determined by density functional theory calculations. The RhB photodegradation mechanism is found to involve hydroxyl radicals in solution formed from photo-generated holes and differs from previous studies performed on nanoparticles and composites.