After studying engineering in the office of John Smeaton, Latrobe entered the office of the London architect S. P. Cockrell in 1789. Two years later he started his own practice. He left England for America in 1795, becoming the country's first professional architect and engineer. His American practice began in Virginia in 1796, but he soon moved to Philadelphia to design its first water system. He is credited with introducing to America the Gothic and Greek revival styles of architecture, both of which would become widespread during the next half century.

From 1803, Latrobe redesigned the interior arrangement and style of the south wing. He also rebuilt and redesigned part of the north wing. After the British burned the Capitol on August 24, 1814, Latrobe was again appointed architect to oversee the necessary restoration work. In a dispute over authority at the Capitol, Latrobe resigned, leaving some of the greatest interiors in the history of neoclassicism in America, including the Hall of the House (now National Statuary Hall), the Old Senate Chamber, and the Old Supreme Court Chamber.