From January to May 1809, Milledge served briefly as President pro tempore of the United States Senate.

[2] At the onset of the Revolutionary War, Milledge was part of a group that took colonial governor Sir James Wright as a prisoner in 1775.

When the British captured Savannah, Milledge escaped to South Carolina, where American patriots nearly hanged him as a spy.

[8] In 1806, he was elected as a Democratic-Republican to the United States Senate to fill the vacancy caused by the death of James Jackson.

[9] While serving in the U.S. House of Representatives, Milledge was named to a commission to establish a site for the state University of Georgia (incorporated January 27, 1785).

On July 25, 1801, Milledge bought with his own money some land[10] on the Oconee River for the school,[11] and named the surrounding area Athens, in honor of the city of Plato's Academy.

John Milledge Hall (circa 1921 as a male dormitory) at the University of Georgia, now houses the Division of Academic Enhancement and the Regents' Center for Learning Disorders.

After retiring from the United States Senate, Milledge returned home, to live out his final years at his plantation near Augusta, Georgia.