The molecular interactions between compound and polymeric carriers are expected to highly contribute to high drug load and good physical stability of solid dispersions. In this study, a series of amorphous solid dispersions (ASD) of Curcumin (Cur) were prepared with different polymers by the solvent evaporation method. With the carrier polyvinylpyrrolidone (PVP), the amorphous solid dispersion system exhibits a better solubility and stability than that with poloxamers and HP-β-CD due to the strong drug-polymer interaction. The drug/polymer interaction and their binding sites were investigated by combined experimental (XRD, DSC, FTIR, SEM, Raman, and 1H-NMR) and molecular dynamics simulation techniques. The Curcumin ASD demonstrated enhanced bioavailability by 11-fold and improved anti-inflammatory activities by the decrease in cytokine production (MMP-9, IL-1β, IL-6, VEGF, MIP-2, and TNF-α) compared to the raw Curcumin. The integration of experimental and modeling techniques is a powerful tool for the rational design of formulation development.