Following George Darwin, he speculated in 1907 that the moon was once a part of the earth and that it broke away where now the Pacific Ocean lies. He also proposed some sort of continental drift (even before Alfred Wegener) and speculated that America, Asia, Africa, and Europe once formed a single continent, which broke up because of the separation of the moon.
In 1908 he made a statement regarding the possibility of airplanes that had not yet been invented, saying that "a popular fantasy is to suppose that flying machines could be used to drop dynamite on the enemy in time of war".
He led solar eclipse expeditions and studied craters on the Moon, and hypothesized that changes in the appearance of the crater Eratosthenes were due to "lunar insects". He claimed to have found vegetation on the moon.
In 1919, he predicted the existence and position of a Planet X based on anomalies in the positions of Uranus and Neptune but a search of Mount Wilson Observatory photographs failed to find the predicted planet. Pluto was later discovered at Flagstaff by Clyde Tombaugh in 1930, but in any case it is now known that Pluto's mass is far too small to have appreciable gravitational effects on Uranus or Neptune, and the anomalies are accounted for when today's much more accurate values of planetary masses are used in calculating orbits. When the planet was named, he interpreted its symbol as a monogram referring to himself and Lowell by the phrase "Pickering-Lowell".
Pickering constructed and established several observatories or astronomical observation stations, notably including Percival Lowell's Flagstaff Observatory. He spent much of the later part of his life at his private observatory in Jamaica. He produced a photographic atlas of the Moon: The Moon : A Summary of the Existing Knowledge of our Satellite — New York: Doubleday, Page & Company, 1903.