He was born in Elizabeth City County, Virginia and educated at home by his mother (his father had died when he was three). He attended the College of William and Mary but dropped out, unable to afford the fees. He read law at the office of Stephen Dewey and was admitted to the bar in Spotsylvania County in 1746. He was Clerk of the committee on Privileges and Elections of the House of Burgesses in 1746, and was appointed Attorney General by the Royal Governor of Virginia in 1753. He served in the House of Burgesses until its dissolution.
He became a Professor of Law at William and Mary (the first professor of Law in America) in 1769, and taught Thomas Jefferson, Henry Clay, James Monroe, and John Marshall.
He was elected to the Continental Congress in 1775, voting in favor of the resolution for independence and signing the Declaration of Independence. He helped form the new government of Virginia and was elected Speaker of the Virginia House of Delegates in 1777. In 1789 he became Judge of the Chancery Court of Virginia.
A slave owner, he became an abolitionist, freeing his slaves and providing for their support. Wythe provided for his slaves in his will, and his other heir, his great-nephew, George Wythe Sweney, decided to avoid this dilution of his fortune by poisoning the slaves with arsenic. In the process, he accidentally killed Wythe as well, though Wythe lingered long enough to change his will to eliminate his bequest to his murderer.
It was the only punishment his killer received. Sweney was acquitted of murder in Virginia, primarily because of a law that forbade the testimony of black witnesses. Sweney was tried for forgery, and convicted, but that was overturned on appeal and Sweney is said to have gone to Tennessee, stole a horse, served a term in a penitentiary, and was then lost to history.