Charles Francis Adams entered politics in the early 1830s as an Anti-Mason, opposing the rites of the Masonic Order as religiously heretical.  After endorsing Democrat Martin Van Buren in the 1836 presidential election, he later found favor with the Whigs for criticizing Van Buren's policies.  Initially Adams believed that the U.S. Constitution protected slavery in the Southern states, but the congressional gag order against antislavery petitions and other events in the late 1830s convinced him otherwise.  He served in the Massachusetts House (1841-1843) and Massachusetts Senate (1843-1845).

In the state legislature, Adams quickly assumed leadership of the antislavery faction that became known as the "Conscience" Whigs (versus the "Cotton" Whigs).  In 1846, he founded the party organ, the Boston Whig, which he edited for its first two years.  When the Whigs nominated slaveowner and Mexican War hero General Zachary Taylor for president in 1848, Adams called for Conscience Whigs to hold their own national convention.  In August, they joined antislavery Democrats to form the Free Soil Party, which opposed the expansion of slavery into the Western territories.  The new party nominated Van Buren for president and Adams for vice president.  They won 10% of the vote and no electoral votes in the November election.

In 1856, Adams joined the new Republican Party, which was also dedicated to halting the expansion of slavery.  In 1858, he was elected as a Republican to the first of two consecutive terms in the U.S. Congress.  In 1860, Adams enthusiastically supported Senator William Henry Seward of New York for the Republican nomination, but dutifully campaigned for Abraham Lincoln in the general election.  During the secession winter of 1860-1861, Adams served on a special House committee established to craft a compromise to save the Union.  After Lincoln appointed Seward as secretary of state, the New Yorker persuaded the president to name Adams as U.S. minister to Great Britain, a position formerly held by his father and grandfather.

Adams faced a difficult situation in London.  Many British officials assumed that Confederate independence was inevitable, that the Civil War could degenerate into a race war, and that the British economy would suffer from prolonged fighting.  A major diplomatic crisis began on November 8, 1861, when a Union ship, the San Jacinto, stopped a British vessel, the Trent, in international waters, and arrested two Confederate diplomats aboard.  Tensions in British rose to a war fever pitch, and the British government demanded an apology.  On December 26, the Lincoln administration agreed to release the men, and a calm Adams explained the American policy to the British, who accepted it as an apology even though, strictly speaking, it was not.

The construction and refitting in British shipyards of vessels used by the Confederate Navy tested Adams's reserve, but he eventually convinced the British government to change their policy.  After the Civil War, much of Adams's time was dedicated to dealing with the conflict caused by American demands that the British government grant financial restitution to the United States for damage done by the British-built Confederate ships; this was known collectively as the Alabama claims.  By the time Adams resigned on April 1, 1868, his diplomacy was well respected in both the United States and Britain.  In 1871, he was appointed as the United States representative at the Geneva tribunal that arbitrated the financial award for the Alabama claims.

Upon returning to the United States in the 1868, Adams became a critic of Radical Republican policies for Reconstruction.  He warned against the centralization of political power, and argued against granting black voting rights until federal troops were withdrawn from the South.  Adams was one of the leading contenders for the presidential nomination at the Liberal Republican Convention on May 1-2, 1872.  He led in the early balloting, but lost to New York Tribune editor Horace Greeley on the sixth ballot.  A number of factors had worked against Adams, including his aloofness, advanced age (65), pro-British views, questionable commitment to reform, and close association with the unpopular Senator Carl Schurz of Missouri.  

In early 1876, Schurz, having returned to the Republican fold, joined Henry Cabot Lodge and other liberals to encourage the Republican Party to nominate Adams for president.  The diplomat was uninterested, though, and the movement never gained momentum.  A few months later, Adams endorsed the Democratic presidential nominee, Samuel J. Tilden, who instructed his supporters in Massachusetts to work for Adams’s nomination for governor.  Although selected by the Massachusetts Democrats, Adams did not want the office and refused to campaign.  Tilden had assumed that having Adams at the top of the Democratic ticket in the Massachusetts would boost his own chances to carry the state in the presidential sweepstakes.  In fact, Adams polled 2500 votes less than Tilden in the November elections, and lost to the Republican nominee, Alexander Hamilton Rice.  A major factor was probably the defection of Irish-Americans, especially in Boston, to the Republican candidate.