An outspoken opponent of slavery, Sumner opposed the Kansas-Nebraska Bill; his 1856 speech "The Crime against Kansas" led to a physical attack on him as he sat at his desk on the floor of Senate by an enraged South Carolina representative. He was absent from his Senate post for the next three years while he recovered from this brutal beating.

On his return to the Senate in 1859, Sumner resumed his denunciations of slavery as a moral evil. In October 1861 he was the first statesman of prominence to urge emancipation. He became chairman of the Senate Foreign Relations Committee in 1861 and aided the Union cause by suppressing resolutions that would have involved the U.S. in war with France and Great Britain.

After the war, Sumner took a prominent part in the movement to impeach President Andrew Johnson, calling him "the enormous criminal" of the century.  He also came into conflict with President Grant on many issues. His opposition to Grant's pet project, the acquisition of Santo Domingo, led to the loss of his chairmanship of the Senate Foreign Relations Committee in 1871.

Sumner died at his residence in Washington on Wednesday, March 11, 1874. His body lay in state in the Rotunda of the Capitol on Friday and was then transported by special railroad cars draped in mourning to Boston. On Sunday, thousands paid their respects to Sumner as his coffin rested in the State House. Monday, March 16th, was the funeral. After a service at King's Chapel, the procession walked five miles to Mount Auburn Cemetery:

"It was nearly six o'clock when the long procession passed under the massive gateway of Mount Auburn, and began its winding march through Central and Walnut and Arethusa Path, to the grave. The officiating clergyman, the pall-bearers, and other gentlemen at the head of the procession, took position about the grave, Mr. Sumner's nearest friends and the Massachusetts Delegation in Congress standing at its foot and a little at the left, with the Committee of the Legislature by their side at the right. At its head, and just behind the minister, were the few surviving members of Mr. Sumner's class in Harvard College; while on the rising slope above and north of the grave stood the Congressional Committee, the members of the Legislature, and invited guests. Behind, clustering on every hillock, and climbing to the very summit of the hill where the Tower stands, was the vast crowd of spectators, numbering many thousands, who waited in silence the last rites of sepulture." - A Memorial of Charles Sumner, 1874