Very little is known about William Pierce's early life. He was probably born in Georgia in 1740, but he grew up in Virginia. During the Revolutionary War Pierce acted as an aide-de-camp to Gen. Nathanael Greene and eventually attained the rank of brevet major. For his conduct at the battle of Eutaw Springs, Congress presented him with a ceremonial sword.

The year Pierce left the army, 1783, he married Charlotte Fenwick of South Carolina. They had two sons, one of whom died as a child. Pierce made his home in Savannah, where he engaged in business. He first organized an import-export company, Pierce, White, and Call, in 1783, but it dissolved less than a year later. He made a new start with his wife's dowry and formed William Pierce & Company. In 1786 he was a member of the Georgia House of Representatives and was also elected to the Continental Congress.

At the Constitutional Convention Pierce did not play a large role, but he exerted some influence and participated in three debates. He argued for the election of one house of the federal legislature by the people and one house by the states; he favored a 3-year term instead of a 7-year term in the second house. Because he agreed that the Articles had been insufficient, he recommended strengthening the federal government at the expense of state privileges as long as state distinctions were not altogether destroyed. Pierce approved of the resulting Constitution, but he found it necessary to leave in the middle of the proceedings. A decline in the European rice market adversely affected his business. Soon after he returned to Savannah he went bankrupt, having "neither the skill of an experienced merchant nor any reserve capital." Only 2 years later, on December 10, 1789, Pierce died in Savannah at age 49 leaving tremendous debts.

Pierce's notes on the proceedings of the convention were published in the Savannah Georgian in 1828. In them he wrote incisive character sketches that are especially valuable for the information they provide about the lesser-known delegates.

The delegate from Georgia, William Leigh Pierce, wrote, "[W]hat is ... remarkable is that every person seems to acknowledge his greatness. Mr. Madison always comes forward the best informed man of any point in debate.