He spent his entire career at Mount Wilson Observatory, where he discovered three more Jovian moons: Lysithea and Carme in 1938, and Ananke in 1951.

He also made a number of eclipse expeditions to measure the brightness and temperature of the Sun's corona.

In the early 1920s, he and Edison Pettit made the first systematic infrared observations of celestial objects.

Their temperatures measurements of nearby giant stars led to some of the first determinations of stellar diameters.

Nicholson, together with astronomer George Ellery Hale, lend their name to the "Hale-Nicholson law" concerning the magnetic polarity of sunspots.