He was born at Philadelphia in 1744, the son of a rich merchant and local politician. Mifflin studied at a Quaker school and then at the College of Philadelphia (now the University of Pennsylvania) and won a diploma. He worked for 4 years in a Philadelphia counting house. He visited Europe in 1764 and entered the mercantile business. In 1767 he married Sarah Morris. Mifflin championed the colonial position against the crown from 1772-1776.

In 1774 he attended the Continental Congress. In 1775 he first became an aide-de-camp to Washington and then Quartermaster General of the Continental Army. One year later he became a colonel and in May 1776 a brigadier general. He took part in the battles of Long Island, NY, Trenton, NJ, and Princeton, NJ. In 1775 he attained the rank of a major general. In 1777-1778, Mifflin sat on the Congressional Board of War.

He returned immediately to politics and sat in the state assembly (1778-1779) and in the Continental Congress from 1782-1784, from December 1783 to June as President. In 1787 he took part in the Constitutional Convention. From 1785-1788 and 1799-1800 he continued on the legislature; chaired the constitutional convention from 1789-1790; and held the governorship from 1790-1799. He died at Lancaster in 1800 at the age of 56.