DNA-induced rate acceleration has been identified as one of the key elements for the success of the DNA-based catalysis concept. Here we report on a novel DNA-based catalytic Friedel-Crafts conjugate addition/enantioselective protonation reaction in water, which represents the first example of a reaction that critically depends on the >700- to 990-fold rate acceleration caused by the presence of a DNA scaffold. The DNA-induced rate acceleration observed is the highest reported due to the environment presented by a biomolecular scaffold for any hybrid catalyst, to date. Based on a combination of kinetics and binding studies, it is proposed that the rate acceleration is in part due to the DNA acting as a pseudophase, analogous to micelles, in which all reaction components are concentrated, resulting in a high effective molarity. The involvement of additional second coordination sphere interactions is suggested by the enantioselectivity of the product. The results presented here show convincingly that the DNA-based catalysis concept, thanks to the DNA-accelerating effect, can be an effective approach to achieving a chemically challenging reaction in water.