Born in Savannah, Georgia, Wayne graduated from Princeton University in 1808, was admitted to the bar in 1810, and began his practice in Savannah. He served in the military during the War of 1812 as an officer in the Georgia Hussars. He served in the Georgia House of Representatives. He then served as the mayor of Savannah from September 8, 1817 to July 12, 1819.
He then served as a Judge in Georgia until he was elected as a Jacksonian to the United States Congress from March 4, 1829, to January 13, 1835. He resigned to accept the appointment as an Associate Justice to the Supreme Court. He served on the court from January 14, 1835 to his death on July 5, 1867. He favored free trade, but opposed internal improvements by Congress, except of rivers and harbors, and opposed the rechartering of the United States Bank.
Wayne died in Washington, D.C., and was interred in Laurel Grove Cemetery, Savannah, Georgia. His sister Mary was the great-grandmother of Juliette Gordon Low, the founder of the Girl Scouts of the USA. In 1831, he sold his home to William Washington Gordon, Juliette's grandfather. This home is now called the Juliette Gordon Low birthplace.