Based on data analyzed from volumetric, viscosimetric measurements and computational simulations, caffeine hydration and aggregation properties in aqueous solutions were compared with caffeine properties in the presence of ATP. The experimental values of the apparent molar volume (Vϕ), apparent molar volume at infinite dilution (Vϕo), Masson's experimental slope (Sv), the apparent molar volume of transfer (ΔtrVϕo), limiting apparent molar expansibility, (Eϕo), hydration number, viscosity B coefficient, thermodynamics parameters of viscous flow were calculated in the temperature range from T = (283.15 to 313.15) K. For the additional investigation of the caffeine hydration properties, the molecular dynamics (MD) simulations, the radial distributive functions (RDFs) and spatial distribution functions (SDFs) were performed. Reduced caffeine hydration and pronounced self-aggregation in the ATP presence are linked to its dehydration effect on caffeine molecules. These results point out the ATP negative effects on caffeine, due to undesirable process of active molecule self-aggregation leading to the reduce bioavailability in the biological systems. Display omitted •The influence of ATP on hydration and self-aggregation properties of caffeine was examined.•The presence of ATP reduces caffeine hydration and promotes its self−aggregation.•The dehydration effect of caffeine was pronounced by ATP.•The local supersaturation of caffeine is the self−aggregation driving force.