In this paper, the solubility of 2-(diacetoxymethyl)-5-nitrofuran in pure methanol, 1-propanol, ethyl acetate, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, acetone, 1,4-dioxane, water, hexane, and toluene and also in (acetonitrile + tetrahydrofuran) binary mixtures with temperatures at T = (278.15–323.15) K at atmospheric pressure was first measured by a gravimetric method. The experimental results reveal that the solubility of 2-(diacetoxymethyl)-5-nitrofuran increases with the increasing temperature in all solvents selected. The modified Apelblat model and the Buchowski–Ksiazaczak λh model were used to correlate the experimental solubility in all pure solvents. Solubility data of (acetonitrile + tetrahydrofuran) binary solvent mixtures were fitted by the Jouyban–Acree model and the combined nearly ideal binary solvent/Redlich–Kister (CNIBS/R-K) model. All the models could be well applied; the modified Apelblat model stood out to be more suitable with a higher accuracy in pure solvent systems, and the combined CNIBS/R-K model provides a superior correlation in the binary solvent systems. The properties of the solute and the solvent were combined, and the Kamlet–Taft linear solvation energy relationship (KAT-LSER) model was used to investigate the solvation effect of 2-(diacetoxymethyl)-5-nitrofuran in the dissolution process. According to the results, the solubility of 2-(diacetoxymethyl)-5-nitrofuran mainly depends on the dipolarity of the investigated solvents, and the proportion of its total solvent effect is 34.3%. We also discussed the effect of the interaction between solvents and solute on solubility. We hope that these experimental data are helpful for technological research and drug purification production.