Tombaugh came from a poor farming background in Streator, Illinois; although he never went to college he managed to teach himself enough of the basic observational skills to be taken on by the Lowell Observatory in Flagstaff, Arizona, in 1929. He transferred to New Mexico in 1955 and served as professor between 1965 and 1973.

Percival Lowell had begun his search for a planet lying beyond the orbit of Neptune in 1905 and this search continued at the Lowell Observatory after his death. Tombaugh was given the job of systematically photographing the sky along the ecliptic where it was thought any trans-Neptunian planet would be found. He used a specially designed wide-field telescope and for each region took two long-exposure photographs separated by several days. He then examined the pairs by means of a blink comparator, an instrument that allows two plates to be alternately observed in rapid succession. Any object that has moved against the background of the stars in the interval between the two exposures will appear to jump backward and forward. Methods were therefore devised for distinguishing asteroids and other moving bodies from the sought-for planet. After a year's observation Tombaugh was able to announce on 13 March 1930 the detection of the new planet, later named Pluto, at a point agreeing closely with the position predicted by Lowell. Pluto was later redefined as a dwarf planet.

The question arose as to whether there were any further trans-Neptunian planets. Consequently Tombaugh continued the search but, although he examined 90 million star images and discovered 3000 asteroids, no other new planet was detected. It is likely that Tombaugh has the honor of discovering the final planet of the solar system.