In this communication, the solubility of digitoxin drug in supercritical CO2 was studied at different operating conditions (311 < T (K) < 343, 120 < P (bar) < 300). The results revealed digitoxin drug solubility (in mole fraction) was between 0.095 × 10−5 to 1.12 × 10−5. In the case of thermodynamic solubility modeling, cubic and non-cubic equation of states i.e. SAFT (statistical associating fluid theory), SRK (Soave-Redlich-Kwong) and sPC-SAFT (simplified perturbed chain SAFT) EoSs and six density-based correlations (Chrastil, Kumar-Johnston (KJ), Mendez-Santiago-Teja (MST), Garlapati and Madras (GM), Bartle et al. and Sung-Shim models) were considered. All used equations indicated reasonable behavior with appropriate accuracy for the solubility of the digitoxin drug. Meanwhile, sPC-SAFT EoS and Kumar-Johnston correlation with AARD% set to 8.96 % and 6.25 %, respectively exhibited greater accuracy in fitting the solubility data. Moreover, total, solvation and vaporization enthalpies of the digitoxin/supercritical carbon dioxide binary mixture were calculated based on KJ, Chrastil and Bartle et al. models.