The effects of solvent and temperature on the complexation of adamantyl mannoside with β‐cyclodextrin and 6‐O‐monotosyl‐6‐deoxy‐β‐cyclodextrin were explored experimentally and by means of molecular dynamics simulations. Efficient binding was observed only in hydrogen‐bonded solvents, which indicated solvophobically driven complexation. The stability of the inclusion complex was considerably higher in aqueous media. A pronounced temperature dependence of ΔrH○ and ΔrS○, resulting in perfect enthalpy–entropy compensation, was observed in water. The complexation thermodynamics was in line with classical rationale for the hydrophobic effect at lower temperatures and the nonclassical explanation at higher temperatures. This finding linked cyclodextrin complexation thermodynamics with insights regarding the effect of temperature on the hydration water structure. The complexation enthalpies and entropies were weakly dependent on temperature in organic media. The signs of ΔrH○ and ΔrS○ were in accordance with the nonclassical hydrophobic (solvophobic) effect. The structures of the optimized product corresponded to those deduced spectroscopically, and the calculated and experimentally obtained values of ΔrG○ were in very good agreement. This investigation clearly demonstrated that solvophobically driven formation of cyclodextrin complexes could be anticipated in structured solvents in general. However, unlike in water, adamantane and the host cavity behaved solely as structure breakers in the organic media explored so far. Favorable guest conditions: The effects of solvent and temperature on the complexation of adamantyl mannoside with β‐cyclodextrin and 6‐O‐monotosyl‐6‐deoxy‐β‐cyclodextrin are explored experimentally and by means of molecular dynamics simulations. Efficient binding is observed only in hydrogen‐bonded solvents, which indicates solvophobically driven complexation.