Defect engineering in metal−organic frameworks (MOFs) has recently become an area of significant research due to the possibility of enhancing material properties such as internal surface area and catalytic activity while maintaining stable 3D structures. Through a modulator screening study, the model Zr 4+ MOF, UiO-66, has been synthesized with control of particle sizes (100−1900 nm) and defect levels (2−24%). By relating these properties, two series were identified where one property remained constant, allowing for independent analysis of the defect level or particle size, which frequently change coincident with the modulator choice. The series were used to compare UiO-66 reactivity for the hydrolysis of a chemical warfare agent simulant, dimethyl 4-nitrophenylphosphate (DMNP). The rate of DMNP hydrolysis displayed high dependence on the external surface area, supporting a reaction dominated by surface interactions. Moderate to high concentrations of defects (14−24%) allow for the accessibility of some interior MOF nodes but do not substantially promote diffusion into the framework. Individual control of defect levels and particle sizes through modulator selection may provide useful materials for small molecular catalysis and provide a roadmap for similar engineering of other zirconium frameworks.