Charles Francis Adams entered public life through opposition to the expansion of slavery. A Massachusetts legislator in the 1840s, he joined the Conscience Whigs and edited the Boston Whig. In 1848 he became the Free Soil Party's vice-presidential candidate on Martin Van Buren's ticket. The campaign failed, but placed him within the movement opposing the extension of slavery into western territories. He later joined the Republicans and served in the United States House of Representatives from 1859 to 1861.

Abraham Lincoln appointed Adams minister to Great Britain in 1861. Throughout the Civil War he worked with Secretary of State William H. Seward to defend Union interests and discourage British recognition of the Confederacy. The Trent crisis tested the relationship when a United States warship removed Confederate envoys from a British mail steamer. Adams helped communicate American intentions while the governments negotiated a settlement and the prisoners were released.

He also protested the construction of Confederate commerce raiders in British shipyards. The Alabama escaped in 1862 and attacked Union merchant shipping, but sustained American pressure helped prevent the delivery of other vessels, including the Laird ironclad rams in 1863. His diplomacy operated alongside military events, British domestic politics and the work of other Union representatives; maintaining British neutrality was a continuing effort rather than a single negotiation.

Adams remained in London until 1868. He subsequently served as the American member of the Geneva arbitration tribunal considering claims arising from British assistance to Confederate cruisers. Its 1872 award required Britain to pay the United States $15.5 million. Alongside politics and diplomacy, he edited family papers, including a ten-volume edition of John Adams's works. These publications and his care of the family collections made historical preservation another enduring part of his career.