Synthesizing micro-/nano-sized pharmaceutical compounds with an appropriate size distribution is a method often followed to enhance drug delivery and reduce side effects. Supercritical CO₂ (carbon dioxide) is a well-known solvent utilized in the pharmaceutical synthesis process. Reliable knowledge of a drug’s solubility in supercritical CO₂ is necessary for feasible study, modeling, design, optimization, and control of such a process. Therefore, the current study constructs a stacked/ensemble model by combining three up-to-date machine learning tools (i.e., extra tree, gradient boosting, and random forest) to predict the solubility of twelve anticancer drugs in supercritical CO₂. An experimental databank comprising 311 phase equilibrium samples was gathered from the literature and applied to design the proposed stacked model. This model estimates the solubility of anticancer drugs in supercritical CO₂ as a function of solute and solvent properties and operating conditions. Several statistical indices, including average absolute relative deviation (AARD = 8.62%), mean absolute error (MAE = 2.86 × 10⁻⁶), relative absolute error (RAE = 2.42%), mean squared error (MSE = 1.26 × 10⁻¹⁰), and regression coefficient (R² = 0.99809) were used to validate the performance of the constructed model. The statistical, sensitivity, and trend analyses confirmed that the suggested stacked model demonstrates excellent performance for correlating and predicting the solubility of anticancer drugs in supercritical CO₂.