Born in Boston, Massachusetts, Lowell graduated from Harvard in 1876. His first interest was oriental studies but Giovanni Schiaparelli's report in 1877 of the ‘canali’ (mistranslated as ‘canals’) of Mars had interested him and he finally decided to devote the rest of his life to astronomy. As he was a member of a famous, aristocratic, and wealthy Boston family, he had no difficulty in financing his own observatory. He built it at a height of 7200 feet (2200 m) in the clear skies of Arizona, giving him good observing conditions, and began his studies of the planets in 1894. He was appointed professor of astronomy at the Massachusetts Institute of Technology in 1902.

Lowell spent 15 years observing Mars with an excellent 24-inch (61-cm) refractor built by Alvan Clark. He had no difficulty in seeing the ‘canals’ of Schiaparelli, also claiming to see oases and clear signs of vegetation. He soon concluded that Mars was inhabited and wrote a series of books on this topic: Mars (1895), Mars and its Canals (1906), and Mars as the Abode of Life (1908). He was by no means alone among professional astronomers in his, what now appears to be extravagant, claim.

It should be realized that large telescopes do little to improve the visual appearance of the planets because of the constantly shifting terrestrial atmosphere. It was not until the Martian surface was mapped by the Mariner and Viking spacecraft in the 1960s and 1970s that the idea of artificial canals could be definitely dispelled.

Lowell was more successful in his work on a trans-Neptunian planet. Even making full allowances for the disturbing effects of Neptune, the orbit of Uranus still was not free from anomalies. Lowell thought that this could be due to an unknown Planet X still further out in space. He calculated its orbit and position, beginning his search in 1905. He published his negative results in 1914. Fourteen years after his death Clyde Tombaugh, observing at the Lowell Observatory in 1930 and using a blink comparator, discovered the new planet. It was named Pluto since like the god it ruled as prince of outer darkness but also because its first two letters stood appropriately for Percival Lowell. Pluto has since been redefined as a dwarf planet.