Enthalpy-entropy compensation was found to be a universal law in protein unfolding based on over 3 000 experimental data. Water molecular reorganization accompanying the protein unfolding was suggested as the origin-of the enthalpy-entropy compensation in protein unfolding. It is indicated that the enthalpy-entropy compensation constitutes the physical foundation that satisfies the biological need of the small free energy changes in protein unfolding, without the sacrifice of the bio-diversity of proteins. The enthalpy-entropy compensation theory proposed herein also provides valuable insights into the Privalov’s puzzle of enthalpy and entropy convergence in protein unfolding. Enthalpy-entropy compensation was found to be a universal law in protein unfolding based on over 3 000 experimental data. Water molecular reorganization accompanying the protein unfolding was suggested as the origin-of the enthalpy-entropy compensation in protein unfolding. It is indicated that the enthalpy-entropy Compensation constitutes the physical foundation that satisfies the biological need of the small free energy changes in protein unfolding, without the sacrifice of the bio-diversity of proteins. The enthalpy-entropy compensation of enthalpy and entropy convergence in protein unfolding.