Van de Hulst studied at the university in his native city of Utrecht where he obtained his PhD in 1946. He spent two years at the University of Chicago as a postdoctoral fellow (1946–48) then took up an appointment at the University of Leiden. Following several years at different universities in America he became professor of astronomy at Leiden and director of the Leiden Observatory.

In the German-occupied Netherlands a group of astronomers began to think about the implications of Grote Reber's discovery of radio emission from the Milky Way. Jan Oort, then director of the Leiden Observatory, wondered whether the emission was merely a uniform noise or could the equivalent of the absorption and emission lines of light be detected. In 1944 van de Hulst came up with the answer.

He proposed that hydrogen atoms, which occur in diffuse but widespread regions in interstellar space, can exist in two forms. In ordinary hydrogen the proton and its orbiting electron spin in the same direction. There is a very small chance that the electron will spontaneously flip over and spin in the opposite direction to the proton and in the process emit radiation with a wavelength of 21 centimeters, i.e., at a frequency of 1420.4 megahertz. Although emission from a single atom is a very rare event, there is such an abundance of hydrogen in the universe that the process should be taking place with sufficient frequency to be detectable.

It was not, however, until 1951 that van de Hulst's proposal was confirmed: the 21-centimeter hydrogen line emission was detected at Harvard by Edward M. Purcell and Harold Ewen who used equipment specially built for the purpose. It has since proved a crucial tool for the investigation of the distribution and movement of neutral hydrogen in our own Galaxy and in other spiral galaxies. Since the hydrogen lies in the spiral arms and since the 21-centimeter emission passes unimpeded through the dust that prevents optical observation, this has led to a greatly increased knowledge of galactic structure.

It was also felt that if intelligent life did exist outside the solar system and wished to communicate with other civilizations, then it would be highly rational to transmit signals at the hydrogen-emission wavelength of 21 centimeter. Although much expensive telescope time has been spent listening on this wavelength, nothing has been heard that does not come from hydrogen itself.