Bruce was born in Prince Edward County, Virginia near Farmville to Pettis Perkinson, a white Virginia plantation owner, and an African American house slave named Polly Bruce. He was treated comparatively well by his father, who educated him together with his legitimate half-brother.
When Blanche Bruce was young, he played with his half-brother. As Blanche Bruce was born enslaved, because of his mother's status, his father legally freed him and arranged for an apprenticeship so he could learn a trade.
In 1850, Bruce moved to Missouri after becoming a printer's apprentice. After the Union Army rejected his application to fight in the Civil War, Bruce taught school and briefly attended Oberlin College in Ohio. Then he went to work as a steamboat porter on the Mississippi River. In 1864, he moved to Hannibal, Missouri, where he established a school for blacks.
During Reconstruction, Bruce became a wealthy landowner in the Mississippi Delta. He was appointed to the positions of Tallahatchie County registrar of voters and tax assessor before winning an election for sheriff in Bolivar County.
He later was elected to other county positions, including tax collector and supervisor of education, while he also edited a local newspaper. In February 1874, Bruce was elected by the state legislature to the Senate as a Republican. In 1880, James Z. George was elected to succeed Bruce.
At the 1880 Republican National Convention in Chicago, Bruce became the first African-American to win any votes at a major party's nominating convention, winning 8 votes for vice president. In 1881, Bruce was appointed by President James A. Garfield to be the Register of the Treasury, making Bruce the first black whose signature was represented on U.S. paper currency.Bruce served as the District of Columbia recorder of deeds in 1891–93, and again as register of the treasury until his death in 1898.