Compartmentalization and binding‐triggered conformational change regulate many metabolic processes in living matter. Here, we have synergistically combined these two biorelevant processes to tune the Diels‐Alder (DA) reactivity of a synthetic self‐complexing host‐guest molecular switch CBPQT4+‐Fu, consisting of an electron‐rich furan unit covalently attached to the electron‐deficient cyclobis(paraquat‐p‐phenylene) tetrachloride (CBPQT4+, 4Cl‐) host. This design allows CBPQT4+‐Fu to efficiently compartmentalize the furan ring inside its host cavity in water, thereby protecting it from the DA reaction with maleimide. Remarkably, the self‐complexed CBPQT4+‐Fu can undergo a conformational change through intramolecular decomplexation upon the addition of a stronger binding molecular naphthalene derivative as a competitive guest, triggering the DA reaction upon addition of a chemical regulator. Remarkably, connecting the guest onto a thermoresponsive lower critical solution temperature (LCST) copolymer regulator controls the DA reaction on command upon heating and cooling the reaction media beyond and below the cloud point temperature of the copolymer, representing a rare example of decreased reactivity upon increasing temperature. Altogether, this work opens up new avenues towards combined topological and supramolecular control over reactivity in synthetic constructs enabling control over reactivity through molecular regulators or even mild temperature variations.