In this study, infrared spectroscopy investigations in combination with DFT calculations were used to elucidate interactions between bosentan monohydrate (BOS) and sildenafil base (SIL) initiated under high energy ball milling. The research was focused mainly on the vibrational properties of their co-milled binary solid dispersions compared to the physical mixtures and single drugs. First, the stability and structure of sildenafil isomers were established. Theoretical infrared spectra were also calculated for trimers and tetramers of bosentan monohydrate and they were compared to the experimental data. The results revealed shifts in wavenumbers, primarily related to the presence of hydrogen bonds, water interactions, and molecular rearrangements during the optimization process of DFT procedure. Second, the infrared spectral analysis was carried out for co-milled binary formulations. The results showed significant changes in their vibrational dynamics related to the amorphization of crystalline drugs. Importantly, it was stated that the amorphous form was stabilized by hydrogen bonds created between BOS and SIL molecules. The classification of the spectra revealed distinct vibrational characteristics typical of binary amorphous solid dispersions. Importantly, the unique spectral classifications differed significantly from those of the corresponding physical mixtures. Finally, it was concluded that the mechanical activation of BOS and SIL base molecules under high energy ball milling resulted in a physical modification of their structure, which could translate into drug dissolution enhancement.