Diflunisal (5-(2,4-Difluorophenyl)salicylic acid, DIF), salicylic acid (SAL) derivative, which, on the one hand, is active pharmaceutical ingredient, on the other hand, belongs to the compounds exhibiting excited-state intramolecular proton transfer (ESIPT) behaviour was used to study the drug interactions with poly(vinyl alcohol) (PVA) matrix. For clarifying the nature and mechanisms of the drug-matrix interactions the salicylic acid (SAL) molecule was selected as the model active ESIPT compound, whose physicochemical properties in different media are well understood. The solute–solvent interactions (non-specific (dipole–dipole) versus specific (hydrogen bonding)) of DIF and SAL with different neat solvents were investigated using the steady-state spectroscopic technique. The solvent effect on spectral behaviours of DIF and SAL was analyzed based on the parametric solvent scales. In order to identify functional groups in the PVA matrices, determine the structure present in the studied molecule-PVA system and thus obtain information about the potential interactions between PVA and the studied molecules, the Raman spectra of pure PVA, SAL-PVA and DIF-PVA systems were measured. It has been shown that the molecular structure of the active substance entrapped in the polymer matrix affects the structure of the polymer, i.e., isotactic (SAL-PVA) versus syndiotactic (DIF-PVA) structure. The analysis of drug release kinetics revealed that the DIF is more strongly bound to PVA in comparison to SAL, which confirms conclusions drawn from the analysis of the Raman spectra i.e., the isotactic structure of SAL-PVA material results in a faster initial release process of weakly bound, located on the surface of the polymer SAL molecules.