Smith attended the common schools. He became engaged in agricultural pursuits and was also a cattle dealer. Later he studied law and was admitted to the bar in 1787. He commenced the practice of his profession in his hometown Woodbury.
In 1789 he became a member of the State house of representatives. He was elected as a Federalist to the Fourth and Fifth Congresses (March 4, 1795-March 3, 1799). Smith declined to be a candidate for renomination in 1798, but served in the State senate from 1800 to 1805. In 1806 he became judge of the supreme court of Connecticut. He kept this position for thirteen years. He also was a delegate to the Hartford Convention of 1814.
Nathaniel Smith died in Woodbury on March 9, 1822. He is intered in the Episcopal Church Cemetery.