Crystallographic perfection in epitaxial thin film heterostructures can eliminate interface defects that dilute unique properties and reduce device performance. However, the requirement for epitaxial perfection greatly limits the selection of material candidates and deposition processes. Using selective interface reactions (SIRs), an atomic layer deposition (ALD)-based technique, we target transformation of undesirable defect sites at imperfect surfaces. Defects on the TiO₂ surface affect the electronic properties, interfaces, and performance of optoelectronic devices that leverage TiO₂ interfaces. We present first principles calculations to predict the difference in hydration/hydroxylation of pristine TiO₂ terraces and minority atomic configurations (i.e. “defects”) including step edges and oxygen vacancies. We investigate hydroxylation differences through temperature dependent scanning tunneling microscopy (STM), and ultimately exploit these differences to selectively react ALD precursors at surface defect sites.