Esomeprazole (ESO) is susceptible to degradation under stress conditions, making polymer selection important for stable solid dispersions. This study evaluated ESO compatibility with five polymers: three grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS-LMP, HPMCAS-MMP, and HPMCAS-HMP), hydroxypropyl methylcellulose phthalate (HPMCP-55), and methacrylic acid–ethyl acrylate copolymer (1:1; Eudragit^® L100-55). Esomeprazole, polymers, and binary mixtures were stored at room temperature and subjected to forced thermal degradation at 60 °C for 16 days. Spectral changes were assessed by visual inspection and attenuated total reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy using the fractional change index (FCI), normalized root-mean-square deviation (NRMSD), and relative maximum spectral difference (relative Max Δ). Density functional theory (DFT) calculations examined interaction energies, non-covalent interactions (NCIs), frontier molecular orbitals, and HOMO–LUMO-based reactivity descriptors. Combining quantitative ATR-FTIR analysis under thermal stress with DFT provides complementary experimental and molecular-level insights into ESO–polymer interactions, including an experimental comparison of three HPMCAS grades. The ESO–HPMCAS-MMP mixture showed the smallest spectral deviations. DFT indicated favorable interactions and relatively low chemical reactivity for the modeled ESO–HPMCAS complex. These findings support the preliminary consideration of HPMCAS-MMP for further formulation studies, although additional evidence is needed to establish comparative chemical compatibility and stability.