Characterization of physical properties of polymorphs in pharmaceuticals is a very important aspect of drug development and manufacturing. This work is to improve the solubility and calculate dissolution thermodynamics of ganciclovir form I. An isothermal saturation method was applied to measure the solubility values of ganciclovir form I in some pure and mixed solvents at temperatures ranging from 278.15 to 318.15 K at atmospheric pressure. The solubility obtained a maximum value in pure 1-butanol and a minimum data in neat toluene. The obtained solubility data of ganciclovir form I in pure solvents were correlated with the modified Apelblat equation, the lambda h equation, and the NRTL model. Meanwhile, the Jouyban-Acree model was applied to simulate ganciclovir form I solubility in binary mixture compositions at various temperatures. The maximum value of the relative average deviation (RAD) was 3.04%, which indicates the experimental data was well consistent with the calculated ones. Apparent thermodynamic analysis indicated that the mixing process in pure solvent is a spontaneous and favorable process. Understanding some physical properties and thermodynamic properties of ganciclovir form I in different solvents is an important aspect of drug development.