The solubility of theobromine was studied both experimentally and theoretically. The solubility was determined spectrophotometrically at 25 °C in neat organic solvents, aqueous binary mixtures, Natural Deep Eutectic Solvents (NADES) and ternary NADES mixtures with water. It was found that addition of water in unimolar proportions with some organic solvents increases theobromine solubility compared to neat solvents. Additionally, using NADES results in a solubility increase of the studied compound not only in relation to water but also DMSO. The addition of water (0.2 molar fraction) to NADES is responsible for an even larger increase of solubility. The measured solubilities were interpreted in terms of three theoretical frameworks. The first one-belonging to the set of data reduction techniques-proved to be very efficient in quantitative back-computations of excess solubility of theobromine in all studied systems. The default approach utilizing the well-recognized COSMO-RS (Conductor-like Screening Model for Real Solvents) framework offered at most a qualitative solubility description. The extended search for possible contacts provided evidence for the existence of many intermolecular complexes that alter the electron density of the solute molecule, thus influencing solubility computations. Taking into account such intermolecular contacts by using the COSMO-RS-DARE (Conductor-like Screening Model for Realistic Solvation-Dimerization, Aggregation, and Reaction Extension) framework seriously increased the accuracy of solubility computations.