A dynamic laser monitoring was used to determined the solubility of 5-fluorouracil at T = (283.15, 288.15, 293.15, 298.15, 303.15, 308.15, 313.15, 318.15 and 323.15) K in 14 solvents, including methanol, water, ethanol, butyric acid, 1-propanol, propionic acid, i-propanol, 1-butanol, acetic acid, i-butanol, formic acid, 1-pentanol, i-amyl alcohol and DMF at P = 0.1 MPa. When the temperature changes from T = (283.15 K − 323.15 K), the solubility values of 5-fluorouracil in 1-butanol, water, ethanol, i-propanol, i-butanol, 1-pentanol, i-amyl alcohol, formic acid, acetic acid, propionic acid, butyric acid, methanol, DMF and 1-propanol were 0.001013–0.003101, 0.001102–0.003452, 0.002022–0.004510, 0.000549–0.002472, 0.000629–0.002615, 0.000791–0.002863, 0.000714–0.002756, 0.000481–0.002382, 0.000413–0.002198, 0.000374–0.002139, 0.000247–0.001427, 0.003130–0.007874, 0.003442–0.014331 and 0.001836–0.004646. It can be seen from the experimental results that the solubility of 5-fluorouracil in all solvents increases with the increase of temperature. Hansen solubility parameter studies the dissolution behavior of 5-fluorouracil in the tested solvents. The Kamlet-Taft parameters were used to discuss the solvent effects. Moreover, the molecular modeling studies were conducted in the paper. Subsequently, the solubility values were corrected by the modified Apelblat equation, Two-Suffix Margules model, NRTL model and Wilson model. Finally, the thermodynamic properties of Gibbs energy, enthalpy and entropy were calculated by the van’t Hoff and Gibbs equations.