Solid-liquid interfaces have been of great significance in the activation of chemical reactions via restricting the conformation or orientation of the reactants. Self-assembled DNA nanostructures encoded with tremendous chemical and physical information provide an efficient platform to unravel and regulate mechanisms of surface chemical processes. In this review, we discuss the surface addressability, morphological features, and charged properties of DNA nanostructures as well as the recognition, catalytic, and dynamic properties of DNA molecules. We highlight the synergies between the surface properties of DNA nanostructures and the molecular features of DNA strands, which is a key to the synthesis of conductive polymer nanomaterials with well-defined shapes or electronic/optical properties. We also focus on the control over the substrate channeling pathways of enzyme networks or metal nucleation on DNA nanostructures toward the production of specifically emissive metal nanoclusters. In the end, we provide an outlook of future possible directions based on the rational design of DNA-based self-assembly, including dynamic energy transfer, stimuli-responsive synthesis, and programmable activation of the mechanophores on the surfaces of DNA nanostructures.