William Harris Crawford was born on 24 February 1772 in Amherst County (now Nelson County), Virginia, the sixth of eleven children of Joel Crawford and Fanny Harris Crawford. Joel's great-grandfather, John, Earl of Crawford, had emigrated to Virginia in 1643. During 1779-83 the family relocated several times, ultimately to Richmond County (now Columbia County), Georgia, near the present site of Appling. After several years of teaching and working on the family farm, Crawford entered Moses Waddell's Carmel Academy near Appling and remained for two years (1792-94), pursuing a curriculum that emphasized Latin, Greek, mathematics, and English grammar and literature. He first studied law during his tenure as a teacher of English at Richmond Academy in Augusta, and in 1799 moved to Lexington in Oglethorpe County to begin practice.

Around 1800 Georgia public life was dominated by the antagonism between two rival Democratic Republican party factions. That associated with John Clark of Wilkes County tended to attract small farmers and land speculators, many of North Carolina origin. That led by James Jackson of Savannah drew its strength from residents of older settled areas, many of them larger landholders moved from Virginia. As Crawford rose to public attention riding Georgia's Western Circuit, his opposition to gross land speculation earned him the enmity of Clark, culminating in several duels (including one fought with Clark himself). It also led to an assumption of leadership within the Jackson faction of the party, alongside George M. Troup.

In 1804 Crawford married Susanna Gerardin (1780-1863), daughter of a Savannah River Valley planter, with whom he would have three daughters and five sons. Around the same time he purchased a tract of land three miles from Lexington that over the years he would expand into a good-sized plantation, called "Woodlawn." At his death he held 1,300 acres and 45 slaves.

Crawford was first elected to public office in 1803, as a state representative from Oglethorpe County. In 1807 the Georgia legislature chose him to fill a vacancy in the U.S. Senate, a position to which he was reelected in 1811. From March 1812 to March 1813 Crawford served as president pro tempore of the Senate. His national stature is evident from the sequence of appointments that came his way over the next several years: U.S. minister to France during the War of 1812 (1813-15); secretary of war in the cabinet of James Madison (1815-16); and secretary of the treasury, a position he held for the remainder of Madison's second term and for the two terms of his successor, James Monroe. (In the March 1816 Republican congressional caucus held to select the party's presidential nominee, Crawford received 54 votes to Monroe's 65, though most today accept as genuine Crawford's disavowal of interest in contesting Monroe).

The Treasury was the largest, and perhaps most inefficient, of Washington's departments. It incorporated the customs service, the land offices, the post office, the internal revenue service, the coastal service, and many other agencies, to say nothing of its necessary relation to the newly established Second Bank of the United States (which Crawford supported). It is generally agreed that Crawford's greatest achievements as secretary were as an administrator, in overhauling and reorganizing the department bureaucracy, and in establishing a greater sense of accountability among its employees. Following the economic collapse of 1819 Crawford and his "Radical" supporters in the administration and Congress led the effort to curb the federal spending associated with the new or nationalist wing of the Republican Party. In an era of increased factionalism within the party, this made him many enemies, including Secretary of War John C. Calhoun and Gen. Andrew Jackson.

Campaigning among leading Republicans for the 1824 presidential election began almost as soon as Monroe was reelected in 1820. Crawford was a favorite, with a platform framed as a return to the virtues of Old Republicanism: strict construction of the Constitution, state sovereignty, fiscal rectitude. His chief opponents were Secretary of State John Quincy Adams, Henry Clay, Jackson, and Calhoun. In September 1823 the fifty-one year old Crawford suffered the onset of a serious illness, described by some as a stroke, whose effects were complicated by the improper ministration of medicines. The limitations imposed by this illness, together with a boycotting of the February 1824 Congressional nominating caucus (a system believed to favor Crawford) undermined his campaign, which ended with Adams's victory in a House vote. Crawford finished behind Jackson and Adams with 41 electoral votes, mostly from Virginia, Georgia, and New York (where he was supported by Martin Van Buren).

Crawford refused reappointment as treasury secretary under Adams and returned to Georgia. His health slowly improved, though he seems to have remained in some respects physically impaired. Though supporters urged him to reenter the national political scene he refrained from doing so, serving as judge of the Northern Circuit of the Superior Court of Georgia. An abiding legacy from his years in Washington was a bitterness towards Calhoun, whom he thought most responsible for keeping him from the presidency. Crawford died near Elberton, Georgia, on 15 September 1834.