Solubility of amlodipine besylate (AMB) in acetonitrile-water mixtures was measured by spectrophotometric technique after equilibration by a well-known shake-flask method. The solubility values were also measured at five temperatures of interests from 293.2 to 313.2 K and 11 mass fractions. The solubility of AMB enhances upon acetonitrile mass fraction increasing and reached its maximum value at 313.2 K with an acetonitrile mass fraction of 0.7. AMB solubility was correlated with different linear and non-linear models with the mean percentage deviations from 2.9% to 49%. The apparent thermodynamic parameters such as enthalpy, entropy, and Gibbs energy were calculated for solvation, dissolution, and mixing processes. The obtained relationship for enthalpy-entropy of AMB showed a non-linear trend in which the enthalpy vs. Gibbs energy plot has positive slope between w1 = 0.00 and w1 = 0.10 of the mixture but negative slop from w1 = 0.10 to w1 = 0.60 and positive slop from w1 = 0.70 to neat acetonitrile. Furthermore, the Jouyban–Acree model was employed to correlated the saturated density values of AMB at different temperatures. Also, by calculating Hansen solubility parameters, it is clear that the dispersion contribution plays the main role in the low solubility of this drug.