Edmund Randolph chose the Revolutionary cause despite his father's loyalism, serving briefly as an aide to George Washington in 1775. Returning to Virginia, he participated in the convention that created the state's first constitution in 1776 and became attorney general. Service in the Continental Congress and election as governor in 1786 placed him among Virginians seeking a stronger national government.

At the Philadelphia Convention in May 1787, Randolph introduced the Virginia Plan, which proposed a national government with separate legislative, executive and judicial branches. He also served on the Committee of Detail, helping turn the convention's decisions into a draft constitution. Yet he refused to sign the final document, objecting to its defects and seeking another opportunity for revision. He later supported ratification in Virginia, judging union under the new framework preferable to the dangers of rejection.

Washington appointed him the first attorney general of the United States in 1789. The office initially involved advising the president and representing the government, with little administrative support. Randolph often attempted to steer between Alexander Hamilton and Thomas Jefferson as divisions within the cabinet hardened. In January 1794 he succeeded Jefferson as secretary of state.

His diplomatic work concerned neutrality in the European war, relations with France, negotiations with Spain and the controversial treaty John Jay negotiated with Britain. In 1795 an intercepted dispatch by French minister Joseph Fauchet was used to accuse him of disloyal conduct and seeking money. Randolph denied wrongdoing, but Washington's confidence had been damaged, and he resigned in August. He published a defence of his conduct and returned to Virginia legal practice. Among his later clients was Aaron Burr during the 1807 treason trial. His career combined an role in constructing the federal government with the personal costs of its first partisan conflicts.