Tetracycline (TTC) is a broad-spectrum antibiotic that has become an emerging contaminant due to its widespread use in human and veterinary medicine. The limited physicochemical data on its solid–liquid equilibrium hinders the development of pharmaceutical formulations and the modeling of its environmental fate. This study aimed to perform a thermodynamic analysis of TTC solubility in ten pure organic solvents between 278.15 and 313.15 K. Solubility was quantified using UV/Vis spectrophotometry and the shaking-flask method. The solid phases at equilibrium were analyzed using FTIR spectroscopy. The apparent standard thermodynamic functions of the solution were calculated using the Gibbs–van’t Hoff–Krug model. The effect of the solvent was evaluated using the KAT-LSER multiparametric model. The results showed that solubility increased with temperature in all studied solvents, reaching its maximum value in N,N-dimethylformamide ($x_2=0.0431$ at 313.15 K) and its minimum in cyclohexane ($x_2$ = $0.00000161$ at 278.15 K), decreasing in alcohols as the aliphatic chain lengthens or becomes branched. We conclude that dissolution is an endothermic process (${\Delta }_{\mathrm{soln}}{H}^{\circ }>0$), favored primarily by enthalpy in polar media, and governed by the dipolarity/polarizability (${\pi }^{*}$) of the solvent.