Educated in England, Lee served in the Virginia House of Burgesses (1758–75). He opposed arbitrary British policies at the time of the Stamp Act and the Townshend Acts, and, with Patrick Henry and Thomas Jefferson, he originated a plan for intercolonial committees of correspondence (March 1777).

Lee was an active member of the First Continental Congress, where admirers of his oratory compared him with Cicero. In the Second Continental Congress he introduced three resolutions: (1) for declaring independence; (2) for forming foreign alliances; and (3) for preparing a plan of confederation. His first resolution was adopted on July 2, and the Declaration of Independence followed two days later. He remained active in Congress until forced to resign in 1779 because of poor health. In 1777, 1780, and 1785 he served in the Virginia House of Delegates and in 1784 was back in Congress, where he remained until 1787, acting as its president in 1784. He opposed ratification of the federal Constitution because it created a “consolidated” government and lacked a bill of rights. He served, nonetheless, as senator from Virginia in the first Congress from 1789 to 1792, when he retired from public life.