We explored the practical advantages and limitations of applying a UiO-66-based metal–organic framework (MOF) catalyst in a flow microreactor demonstrated by the catalytic hydrolysis of ethyl paraoxon, an organophosphorus chemical agent. The influences of the following factors on the reaction yield were investigated: a) catalyst properties such as crystal size (14, 200, and 540 nm), functionality (NH2 group), and particle size, and b) process conditions: temperature (20, 40, and 60 °C), space times, and concentration of the substrate. In addition, long-term catalyst stability was tested with an 18 h continuous run. We found that tableting and sieving is a viable method to obtain MOF particles of a suitable size to be successfully screened under flow conditions in a microreactor. This method was used successfully to study the effects of crystal size, functionality, temperature, reagent concentration, and residence time. Catalyst particles with a sieved fraction between 125 and 250 µm were found to be optimal. A smaller sieved fraction size showed a major limitation due to the very high pressure drop. The low apparent activation energy indicated that internal mass transfer may exist. A dedicated separate study is required to assess the impact of pore diffusion and site accessibility.