Temperature dependent solubility data of tadalafil (TDL) in diethylene glycol monoethyl ether (Transcutol) + water co-solvent mixtures are not available in literature. Therefore, the aim of present study was to determine the temperature dependent solubility data of crystalline TDL in mono-solvents and various Transcutol + water co-solvent mixtures from 298.15 to 333.15 K at atmospheric pressure. The experimental solubilities of crystalline TDL were measured using the shake flask method. The experimental solubilities were correlated with the Apelblat model. The solubilities of crystalline TDL were regressed by Apelblat equation with a relative deviation in the range of 0.02 to 6.81% in all co-solvent mixtures investigated at 298.15 to 333.15 K. The root mean square deviations were observed in the range of 0.013 to 0.058. However, the correlation coefficients were observed in the range of 0.996 to 0.999. The solubility of crystalline TDL was found to be increased with increase in temperature and mass fraction of Transcutol in co-solvent mixtures. The mole fraction solubility of crystalline TDL was observed highest in pure Transcutol (8.76×10−3 at 298.15 K) as compared to water (5.74×10−7 at 298.15 K). Around 15,263 fold enhancements in solubility of crystalline TDL in Transcutol were observed as compared to its aqueous solubility at 298.15 K. The dissolution of TDL in most of the co-solvent mixtures was assumed to be non-spontaneous, endothermic and an entropy driven process. Overall, the results of these studies indicated that Transcutol could be used as a co-solvent in formulation development especially in terms of liquid dosage forms of crystalline TDL.