A member of the distinguished Lowell family of Massachusetts (he was brother to A. Lawrence Lowell and Amy Lowell), he devoted himself (1883–93) to literature and travel, much of the time in the Far East, which he described in Chosön (1886), The Soul of the Far East (1888), Noto (1891), and Occult Japan (1895). During part of this time he was counselor and foreign secretary to the Korean Special Mission to the United States.

In the 1890s, inspired by Giovanni Schiaparelli's discovery of “canals” on Mars, Lowell decided to devote his fortune and energy to the study of Mars. After careful consideration of desirable sites, he built a private observatory at Flagstaff, Ariz. Lowell championed the now-abandoned theory that intelligent inhabitants of a dying Mars constructed a planet-wide system of irrigation, utilizing water from the polar ice caps, which melt annually. He thought the canals were bands of cultivated vegetation dependent on this irrigation. Among his many books on this subject is Mars and Its Canals (1906). Lowell's theory, long vigorously opposed, was finally put to rest by information received from the U.S. spacecraft Mariner 4 when it flew past Mars in July 1965.

Early in the 20th century Lowell made an elaborate mathematical study of the orbit of Uranus. He attributed certain irregularities to the action of an unseen planet beyond Neptune and calculated its probable position. In 1905 he organized a systematic search for the planet by the staff of his observatory, and in 1915 he published his “Memoir on a Trans-Neptunian Planet.” Fourteen years after his death the search culminated in the discovery of Pluto.