The aqueous mixture of 2,2,2-trifluoroethanol (TFE) is one of the important alcoholic solvents which has been extensively used for understanding the stability of proteins as well as several chemical reactions. In this paper, the deconvolution of the IR lines in the OH-stretching region has been applied to understand the local structure of water-water, alcohol-water, and alcohol-alcohol interactions in the water mixture of TFE and ethanol (ETH). Further, molecular dynamics simulations, quantum chemical calculations, and atoms in molecules analysis have been performed to encode the local structure information obtained from the experimental data. Addition of a small amount of alcohol in a pure aqueous medium enhances the aggregation of water molecules for the case of ETH, whereas the hydrogen bond between TFE and water is the dominant contributor for TFE. The -CF3 substitution changes the orientation and hydrogen-bonding site of water molecules from the hydrophilic OH terminal to the hydrophobic -CF3 terminal of TFE, which decreases the clustering of water molecules as well as enhances the hydrogen bonding between TFE and water. In the TFE-rich region of the water mixture of TFE, the fluorine of the TFE molecules interacts with each other through a weak fluorous interaction which reduces the hydrogen bonding between the -CF3 of TFE and water molecules. These findings about the hydrogen bond network of the water mixture of TFE induced by the hydrophobic -CF3 group provide a stepwise explanation of the unique hydrophobic properties of the trifluoromethyl group containing pharmaceutical molecules.