Two years after his graduation (1807) in law from the College of William and Mary, Crittenden became territorial attorney general in Illinois. During the War of 1812, having returned to Kentucky, he was elected to the legislature of that state. Later he served intermittently in the U.S. Senate, from 1817 through 1861.

Crittenden left the Senate in 1840 to become U.S. attorney general in William Henry Harrison's Whig administration but resigned, along with others, after John Tyler, having acceded to the presidency on Harrison's death (April 4, 1841), had vetoed a national banking act favoured by the Whigs.

Crittenden returned to the Senate in 1842 and left again to serve as governor of Kentucky (1848–50). During his last years in the Senate (1855–61), the controversial Kansas-Nebraska Act of 1854, enunciating the doctrine of local option in the territories concerning slavery, led to the breakup of the Whig Party, whereupon Crittenden first joined the American, or Know-Nothing, Party (1856) and then switched to the Constitutional Union Party (1859), which sought to unite the sections by ignoring the slavery issue.

After Abraham Lincoln's election, Crittenden introduced his resolutions (December 1860) proposing a collection of compromises on the slavery issue, but they were defeated, and he went home to try to save Kentucky for the Union. In May 1861 he was chairman of the Frankfort convention of border-state leaders that asked the South to reconsider its position on secession from the Union. He then returned to Congress as a representative. One of his sons, Thomas, was a major general in the Union Army; another son was a major general in the Confederate Army.