Born in Springfield, Massachusetts, Benjamin Wade's first job was as a laborer on the Erie Canal. He also taught school before studying law in Ohio. After being admitted to the bar in 1828, he began his work as a lawyer in Jefferson, Ohio.

Wade eventually formed a partnership with Joshua Giddings, a prominent anti-slavery figure. As a member of the Whig Party, Wade was elected to the Ohio State Senate, serving two two-year terms between 1837 and 1842. Between 1847 and 1851, Wade was a judge in an Ohio court.

After the decline of the Whigs' power, Wade joined the Republican Party, and in 1851 he was elected to the United States Senate. There, he associated with such eventual Radical Republicans as Thaddeus Stevens and Charles Sumner. He fought against the controversial Fugitive Slave Act and the Kansas-Nebraska Act. He was one of the most radical politicians in America at that time, supporting women's suffrage, trade union rights, and equality for African-Americans. He was also critical of capitalism.

In July 1861, Wade, along with other politicians, witnessed the defeat of the Union Army at the 1st Battle of Bull Run. There, he was almost captured by the Confederate Army. After arriving back at Washington, he was one of those who led the attack on the supposed incompetence of the leadership of the Union Army. From 1861 to 1862 he was chairman of the important Joint Committee on the Conduct of the War, and in 1862, as chairman of the Senate Committee on Territories, was instrumental in abolishing slavery in the Federal Territories.

During the American Civil War, Wade was highly critical of President Abraham Lincoln; in a September 1861 letter, he privately wrote that Lincoln's views on slavery "could only come of one born of poor white trash and educated in a slave State." He was especially angry when Lincoln was slow to recruit African-Americans into the armies.

Wade was also critical of Lincoln's Reconstruction Plan; in 1864, he and Henry Winter Davis sponsored a bill that would run the South, when conquered, their way. The Wade-Davis Bill passed on July 2, 1864, with only one Republican voting against it. However, President Lincoln refused to sign it, later stating that he didn't want to be held to one Reconstruction policy.

Wade, along with most other Radical Republicans, was highly critical of President Andrew Johnson (who became President after Lincoln's assassination). At the beginning of the 40th Congress, Wade became the President pro tempore of the U.S. Senate, which meant that he was next in line for the presidency (as Johnson had no vice president).

After many fallouts with the Republican-dominated Congress, the Judiciary Committee voted to impeach President Johnson (who was a Democrat). Although most senators believed that Johnson was guilty of the charges, they did not want the extremely radical Wade to become president. The votes resulted in one less than the large majority required. One newspaper wrote, "Andrew Johnson is innocent because Ben Wade is guilty of being his successor."

In 1868, then-presidential candidate Ulysses S. Grant was urged by his fellow Republicans to choose Wade as his vice president; but he refused, instead choosing another radical (Schuyler Colfax). After being defeated in the 1868 elections, Wade returned to his Ohio law practice. He died on March 2, 1878, in Jefferson, Ohio.