This study evaluated the performance of alternative green solvents, i.e. D-limonene, dimethylcarbonate (DMC), ethanol, ethyl acetate, ethyl lactate and methyltetrahydrofuran (MeTHF) compared to the petroleum based dichloromethane, for extraction of alpha-mangostin from Garcinia mangostana pericarps. The Hansen solubility parameters (HSPs) were used to explain the dissolution behavior of the solutes and solvents, and the conductor-like screening model for realistic solvation. The (COSMO-RS), a statistical thermodynamic approach based on the results of quantum chemical calculations for comprehending the dissolving mechanisms were used to predict the extraction prediction. On the basis of the Hansen analysis, dichloromethane was the most suitable solvent for extraction of alpha-mangostin. However, COSMO-RS analysis showed a higher solubility of alpha-mangostin in ethyl lactate, DMC, MeTHF, ethyl acetate and ethanol. Moreover, the experimental studies using a classical reflux extraction followed by a quantitative HPLC analysis of alpha-mangostin showed similar results to the predictive values from the COSMO-RS model. The alpha-mangostin levels extracted by ethyl lactate, DMC, MeTHF, ethyl acetate and ethanol were higher than those using dichloromethane and D-limonene. The results support the potential use of ethyl lactate, DMC, MeTHF, and ethanol as alternative green solvents for the preparation of alpha-mangostin extracts.