AbstractMulticompartment micelles (MCMs) containing acid and base sites in discrete domains are prepared from poly(norbornene)‐based amphiphilic bottlebrush copolymers in aqueous media. The acid and base sites are localized in different compartments of the micelle, enabling the nonorthogonal reaction sequence: deacetalization – Knoevenagel condensation – Michael addition of acetals to 2‐amino chromene derivatives. Computational simulations using dissipative particle dynamics (DPD) elucidated the bottlebrush composition required to effectively site‐isolate the nonorthogonal catalysts. This contribution presents MCMs as a new class of nanostructures for one‐pot multistep nonorthogonal cascade catalysis, laying the groundwork for the isolation of three or more incompatible catalysts to synthesize value‐added compounds in a single reaction vessel, in water.