He studied under Sir James Thornhill, and in 1728 accompanied Bishop Berkeley to America, with the intention of becoming professor of fine arts in the college which Berkeley was planning to found in Bermuda. The college, however, was never established, and Smybert settled in Boston, where he married in 1730.
In 1731 he painted "Dean George Berkeley and His Family," now in the Yale University Art Gallery, Yale University, a group of eight figures; it is maintained that the person furthest to the left is actually the artist himself. He painted portraits of Jonathan Edwards and Judge Edmund Quincy (in the Boston Art Museum), Mrs Smybert, Peter Faneuil and Governor John Endecott (in the Massachusetts Historical Society), John Lovell (Memorial Hall, Harvard University), and probably one of Sir William Pepperrell; and examples of his works are owned by Harvard and Yale Universities, by Bowdoin College, by the Massachusetts Historical Society, and by the New England Historical and Genealogical Society.
Between 1740-42, he served as architect for the original Faneuil Hall, which he designed in the style of an English country market. The hall burned down in 1761 but was restored, and then in 1806 greatly expanded and modified by Charles Bulfinch.