Mifflin was born in Philadelphia, Pennsylvania, in 1744. He graduated from college in 1760, entered a counting house, travelled in Europe in 1765, and on his return engaged in commercial business in partnership with a brother.
Early in the Revolutionary War, Mifflin left the Continental Congress to serve in the Continental Army. He was commissioned a major, then became George Washington's aide-de-camp and, on August 14, 1775, became the army's first Quartermaster General. He was good at the job, but preferred to be on the front lines. His leadership in battle gained him promotions to colonel and then brigadier general. He asked to be relieved of the job of quartermaster-general, but was then persuaded to resume those duties because Congress was having trouble finding someone to replace him.
Mifflin served on the Congressional Board of War from 1777 to 1778, then rejoined the army, but took little active role, because of criticism of his service as quartermaster general. He was accused of embezzlement, and welcomed an inquiry, which never took place. He resigned his commission--by then, as a major general--but Congress continued to ask his advice even after accepting his resignation.
In the course of his career, Mifflin held a number of political offices. He was a member of the colonial Pennsylvania legislature; served twice terms in the Continental Congress (1774 - 1775, and 1782 - 1784); and served in the Pennsylvania House of Representatives (1785 - 1788). He was a delegate to the United States Constitutional Convention in 1787, and a signer of the United States Constitution. He then served as President of the Supreme Executive Council of Pennsylvnia (October 1788 - October 1790), President of the State Constitutional Convention 1790, and governor of Pennsylvania from 1790 to 1799, finally returning to the state legislature until his death, in Lancaster, Pennsylvania, January 20, 1800.
Mifflin County, Pennsylvania is named for him.