This study aims to evaluate the performance of a new hybrid solvent, comprising aqueous MDEA and tetrabutylphosphonium trifluoroacetate ([TBP][TFA]), for CO2 capture and to optimize its CO2 absorption efficiency. First, this study focused on predicting the thermodynamic properties of aqueous MDEAs and [TBP][TFA] and their interaction energy with CO2 using COSMO-RS. Based on the prediction, it aligns with the principle that CO2 solubility in the MDEA-[TBP][TFA] hybrid solvent decreases as the Henry’s Law constant increases, with the interactions primarily governed by van der Waals forces and hydrogen bonding. The aqueous MDEA-[TBP][TFA] hybrid solvent was prepared in two steps: synthesizing and blending [TBP][TFA] with aqueous MDEAs. The formation and purity of [TBP][TFA] were confirmed through NMR, FT-IR, and Karl Fischer. The heat capacity of the hybrid solvents was lower than their aqueous MDEA solutions. The performance and optimization of CO2 capture were studied using RSM-FC-CCD design, with the optimal value obtained at 50 wt.% MDEA, 20 wt.% [TBP][TFA], 30 °C, and 30 bar (12.14 mol/kg), aligning with COSMO-RS predictions. A 26% reduction in the heat capacity was achieved with the optimal ratio (wt.%) of the hybrid solvent. These findings suggest that the aqueous MDEA-[TBP][TFA] hybrid solvent is a promising alternative for CO2 capture, providing a high removal capacity and lower heat capacity for more efficient regeneration compared to commercial aqueous MDEA solutions.