One of the key factors of Alzheimer's disease (AD) is the conversion of amyloid beta-peptide (A beta) from its soluble random coil form into various aggregated forms. (-)-Epigallocatechin-3-gallate (EGCG) has been proved effective in preventing the aggregation of A beta, but the thermodynamic mechanisms are still unclear. In this work, isothermal titration calorimetry (ITC) was utilized to study the interactions between A beta 42 and EGCG at different temperatures, salt concentrations, pH values, and EGCG and A beta 42 concentrations. Molecular dynamics (MD) simulations were performed to study the hydrogen bonding between A beta 42 and EGCG. The results indicate that the binding stoichiometry N is linearly related to the EGCG/A beta 42 ratio. Hydrophobic interaction and hydrogen bonding are both substantial in the binding process, but the extent of their contributions changes with experimental conditions. Namely, the predominant interaction gradually shifts from a hydrogen bonding to a hydrophobic interaction with the increase of the EGCG/A beta 42 ratio, resulting in a transition of the binding from enthalpy-driven to entropy-driven. This experimental observation is validated by the MD simulations. The binding of EGCG to A beta 42 can be promoted by increasing temperature and salt concentration and changing pH away from A beta 42's pI. The findings have provided new insight into the molecular interactions between A beta 42 and EGCG from a thermodynamic perspective and are expected to facilitate the research on the inhibition of A beta 42 aggregation.