Admitted to the Ohio bar in 1842, Vallandigham was elected to the state legislature in 1845. While a member of the U.S. House of Representatives (1857–63), he was adamant against the principles and policies of the newly formed Republican Party, particularly as they related to the slavery issue. Of Southern ancestry, he idealized the Southern way of life, and he assumed leadership of the faction of Midwest Democrats, called Copperheads, who opposed the prosecution of the war against the South—a war they viewed as beneficial only to Eastern interests.

During the Civil War he bitterly attacked the administration of President Abraham Lincoln, charging that it was destroying not only the Constitution but civil liberty as well. He also became commander of the secret, antiwar Knights of the Golden Circle (later Sons of Liberty). In 1863 he made vigorous speeches in Ohio against the war and the government and consequently grew to be one of the most suspected and hated men in the North. He was arrested in May by military authorities for expressing treasonable sympathy with the enemy; tried and found guilty by a military commission, he was sentenced to imprisonment. Soon afterward Lincoln commuted his sentence to banishment behind Confederate lines.

Bored with exile in the South, Vallandigham made his way to Canada, where he continued his campaign of harassment from across the border. In September 1863 the Ohio Peace Democrats nominated him in absentia for governor, but resounding Union military victories at Gettysburg and Vicksburg in July ensured his decisive defeat at the polls. He returned illegally to Ohio in 1864 and took an active part in that year's election campaign. He also wrote part of the national Democratic platform in which the war was denounced as a failure.

After the war Vallandigham criticized the Radical Reconstruction policy of the Republicans as both unconstitutional and tyrannical, but in 1870 he recognized the uselessness of further opposition and urged his party to emphasize financial issues instead. He died the following year after accidentally shooting himself with a firearm that was an exhibit in a murder trial.