Read's mother was the daughter of a Welsh planter, and his Dublin-born father a landholder of means. Soon after George's birth in 1733 near the village of North East in Cecil County, MD, his family moved to New Castle, DE, where the youth, who was one of six sons, grew up. He attended school at Chester, PA, and Rev. Francis Alison's academy at New London, PA, and about the age of 15 he began reading with a Philadelphia lawyer.

In 1753 Read was admitted to the bar and began to practice. The next year, he journeyed back to New Castle, hung out his shingle, and before long enlisted a clientele that extended into Maryland. During this period he resided in New Castle but maintained Stonum a country retreat near the city. In 1763 he wed Gertrude Ross Till, the widowed sister of George Ross, like Read a future signer of the Declaration of Independence. She bore four sons and a daughter.

While crown attorney general (1763-74) for the Three Lower Counties (present Delaware), Read protested against the Stamp Act. In 1765 he began a career in the colonial legislature that lasted more than a decade. A moderate Whig, he supported nonimportation measures and dignified protests. His attendance at the Continental Congress (1774-77) was irregular. Like his friend John Dickinson, he was willing to protect colonial rights but was wary of extremism. He voted against independence on July 2, 1776, the only signer of the Declaration to do so, apparently either bowing to the strong Tory sentiment in Delaware, or believing reconciliation with Britain was still possible.

That same year, Read gave priority to state responsibilities. He presided over the Delaware constitutional convention, in which he chaired the drafting committee, and began a term as speaker of the legislative council, which in effect made him vice president of the state. When the British took Wilmington the next fall, they captured the president, a resident of the city. At first, because Read was away in Congress, Thomas McKean, speaker of the lower house, took over as acting president. But in November, after barely escaping from the British himself while he and his family were en route to Dover from Philadelphia, newly occupied by the redcoats, Read assumed the office and held it until the spring of 1778. Back in the legislative council, in 1779 he drafted the act directing Delaware congressional delegates to sign the Articles of Confederation.

During 1779, in poor health, Read resigned from the legislative council, refused reelection to Congress, and began a period of inactivity. During the years 1782-88, he again sat on the council and concurrently held the position of judge of the court of appeals in admiralty cases.

Meantime, in 1784, Read had served on a commission that adjusted New York-Massachusetts land claims. In 1786 he attended the Annapolis Convention. The next year, he participated in the Constitutional Convention, where he missed few if any sessions and championed the rights of the small states. Otherwise, he adopted a Hamiltonian stance, favoring a strong executive. He later led the ratification movement in Delaware, the first state to ratify.

In the U.S. Senate (1789-93), Read's attendance was again erratic, but when present he allied with the Federalists. He resigned to accept the post of chief justice of Delaware. He held it until his death at New Castle 5 years later, just 3 days after he celebrated his 65th birthday. His grave is there in the Immanuel Episcopal Churchyard.