Nonionic kosmotropes are polyols or carbohydrates whose addition to an aqueous solution raises the order of the solvent and changes its properties without interacting significantly with other existing solutes. The presence of kosmotropes was previously proven as a stabilizing factor for protein structure under thermal treatment. We chose to study the kosmotropic effect on structural influences of high-hydrostatic pressure (HHP) on proteins. Additionally, the effect of HHP on interactions between macromolecules and hydrophobic nutraceuticals is not fully understood. In this research, we studied the effect of HHP on protein-flavonoid interactions using a series of flavonoids differing by small structural differences. We focused on the effect of sucrose as a model nonionic kosmotrope on the protein structure and its interaction with flavonoids. Despite results indicating the importance of hydrophobic bonds, the effect of flavonoid structure on protein interactions suggests a crucial effect of molecular flexibility and polar bond importance. A kosmotropic stabilizing effect was seen on the pressure unfolding of the protein, also affecting the protein-flavonoid interaction. The extent of the kosmotropic effect was dependent on the flavonoid structure.