Clark, the son of the instrument-maker Alvan Clark, was born at Fall River, Massachusetts. He started life as a portrait painter but soon joined his father's firm and became a lens grinder, preparing the mirrors and lenses for some of the best telescopes of the late 19th century. In 1861 he had made a lens for Edward Barnard at the University of Mississippi. Testing it before parting with it he looked through it at Sirius and to his surprise observed a faint image near the star. It was, in fact, Sirius B, the famous companion predicted by Friedrich Bessel in 1844. Clark made many more observations, and discovered 16 double stars.

The Clark firm provided Simon Newcomb, head of the US Naval Observatory, with a 26-inch (66-cm) refractor. It was with this that the very small satellites of Mars, Phobos, and Deimos were detected by Asaph Hall in 1877. In 1888 Clark built the 36-inch (91-cm) refractor for the Lick Observatory and his final achievement, just before his death, was to install his 40-inch (101-cm) refractor in the Yerkes Observatory. A practical limit is reached in using lenses larger than this and after Clark's death astronomers put their faith in mirrors rather than lenses. For this reason the Yerkes 40-inch and the Lick 36-inch are still the largest and the second largest refractors in the world.