Reed practiced law in Philadelphia before entering the revolutionary movement through the city’s Committee of Correspondence. In 1775 he joined Washington's military staff as secretary, handling the army’s correspondence. He became adjutant general in 1776 and participated in the campaigns around New York and New Jersey, including preparations for the attack on Trenton. His private doubts about Washington, expressed in correspondence with Charles Lee, briefly strained their relationship.

In 1777 Reed shifted toward civil office, representing Pennsylvania in the Continental Congress and signing the Articles of Confederation. From 1778 to 1781 he served as president of Pennsylvania's Supreme Executive Council, the state’s executive position. He worked on military supplies, public finance and support for soldiers, and his administration participated in the adoption of Pennsylvania's gradual abolition law in 1780.

Reed also pursued charges against Benedict Arnold during Arnold's command at Philadelphia, contributing to a public dispute over the use of military authority and private business. In January 1781 he helped negotiate with mutineers of the Pennsylvania Line over enlistments, arrears and conditions of service. After leaving the executive council he returned to law. Elected to Congress again in 1784, he did not attend because of declining health and died the following year. His public career moved between the army's headquarters and Pennsylvania's wartime government.