The mole fraction solubility of amoxicillin in four co-solvent mixtures of N,N-dimethylformamide (DMF) + water (2), isopropanol (1) + water (2), N-methyl pyrrolidone (NMP) (1) + water (2) and ethylene glycol (EG, 1) + water (2) at temperatures from 278.15 K to 328.15 K was determined by means of the shake-flask technique. At the same temperature and composition of DMF, isopropanol, NMP or EG, the solubility magnitude of amoxicillin was highest in the DMF (1) + water (2) mixture, and lowest in the isopropanol (1) + water (2) mixture. Through the Jouyban-Acree model, amoxicillin solubility was well correlated obtaining RAD lower than 4.55% and RMSD lower than 1.96 × 10-4. Quantitative values for the local mole fraction of DMF (isopropanol, NMP or EG) and water nearby the amoxicillin were computed by means of the Inverse Kirkwood–Buff integrals method. In the DMF (1) + water (2) mixture with compositions 0.20 < x1 < 1.00, NMP (1) + water (2) mixture with compositions 0.165 < x1 < 1.00 and EG/isopropanol (1) + water (2) mixtures with compositions 0.25 < x1 < 1.00, amoxicillin was solvated preferentially by the co-solvent. In addition, solvent effect was modeled by linear solvation energy relationships in terms of KAT solvent polarity descriptors to detect the main intermolecular interactions controlling the solubility variation in solvent mixtures. Results showed that the work for cavity formation in solvent for solute’s accommodation had the most significant effect on solubility variance over the entire composition range in all the mixed solvents.