Girard shipped out to sea at the age of 14 and by 1774 was captain of a ship involved in U.S. coastal trade with the West Indies. Stymied by British blockades of U.S. seaports during the Revolutionary War (1775–83), he settled in Philadelphia but resumed maritime trading after the war. He developed a worldwide trading fleet and scrupulously efficient business methods that laid the foundation of his fortune. In 1812 he bought out the first Bank of the United States, after its charter had expired. He renamed it the Bank of Stephen Girard, which became known as the “sheet anchor” of government credit during the War of 1812. Toward the end of the war, when U.S. credit was at its lowest ebb, his subscription for 95 percent of the government war loan issue enabled the United States to carry on the war. Subsequently he was one of Philadelphia's most noted civic leaders.

Girard bequeathed nearly his entire fortune to social welfare institutions, including an endowment for a Philadelphia college for male orphans, founded as the Stephen Girard College in 1833.