<p>Non-covalent interactions are central to the organization of matter and molecular recognition processes, yet they are difficult to characterize. Here we devise a platform strategy to systematically build non-covalent interactions with selective chemical groups into precisely designed configurations by using metal–organic frameworks (MOFs) as the molecular scaffold. Using the vibrational Stark effect benchmarked against computer models, we find the electric field provides a unifying metric for quantifying diverse non-covalent interactions in MOFs and solvation environments. We synthesize and analyse spectroscopically a collection of non-covalent interactions using a nitrile probe within the MOF structure, and identify stabilizing fields as strong as −123 MV cm⁻¹ produced additively by multiple hydrogen bonds, an unusual destabilizing field of +6 MV cm⁻¹ between antiparallel dipoles, anomalous hydrogen-bond blueshifts as large as 34 cm⁻¹ and unique solvation under nanoconfinement. This method for making and testing non-covalent interactions opens new avenues for exploring non-covalent interactions.</p><p></p>