The NOE developed from the theoretical work of American physicist Albert Overhauser who in 1953 proposed that nuclear spin polarization could be enhanced by the microwave irradiation of the conduction electrons in certain metals.  The electron-nuclear enhancement predicted by Overhauser was experimentally demonstrated in Li metal by T. R. Carver and C. P. Slichter also in 1953. A general theoretical basis and experimental observation of an Overhauser effect involving only nuclear spins in the HF molecule was published by Ionel Solomon in 1955.   Another early experimental observation of the NOE was used by Kaiser in 1963 to show how the NOE may be used to determine the relative signs of scalar coupling constants, and to assign spectral lines in NMR spectra to transitions between energy levels. In this study, the resonance of one population of protons (H) in an organic molecule was enhanced when a second distinct population of protons in the same organic molecule was saturated by RF irradiation. The application of the NOE was used by Anet and Bourn in 1965 to confirm the assignments of the NMR resonances for &beta;,&beta;-dimethylacrylic acid and dimethyl formamide, thereby showing that conformation and configuration information about organic molecules in solution can be obtained. Bell and Saunders reported direct correlation between NOE enhancements and internuclear distances in 1970  while quantitative measurements of internuclear distances in molecules with three or more spins was reported by Schirmer et al.
Richard R. Ernst was awarded the 1991 Nobel Prize in Chemistry for developing Fourier transform and two-dimensional NMR spectroscopy, which was soon adapted to the measurement of the NOE, particularly in large biological molecules. In 2002, Kurt Wuthrich won the Nobel Prize in Chemistry for the development of nuclear magnetic resonance spectroscopy for determining the three-dimensional structure of biological macromolecules in solution, demonstrating how the 2D NOE method (NOESY) can be used to constrain the three-dimensional structures of large biological macromolecules. Professor Anil Kumar was the first to apply the two-dimensional Nuclear Overhauser Effect (2D-NOE now known as NOESY) experiment to a biomolecule, which opened the field for the determination of three-dimensional structures of biomolecules in solution by NMR spectroscopy.