He was born near Versailles, Kentucky, and attended Washington College (now Washington and Lee University) in Lexington, Virginia, and graduated from William and Mary College in 1806. Thereafter he studied law and was admitted to the bar and commenced practice in Woodford County, Kentucky in 1807.

He was attorney general of Illinois Territory from 1809-1810; served in the War of 1812 as an aide to the governor; and resumed the practice of law in Russellville, Kentucky after the end of the war.

He served in the Kentucky House of Representatives from 1811 to 1817, and served as Speaker of the House during his last term in that body. He was elected to the United States Senate and served from March 4, 1817, to March 3, 1819, when he resigned. During his tenure in the 15th Congress he served as chairman of the U.S. Senate Committee on Judiciary.

After leaving Congress he moved to Frankfort, Kentucky. He briefly rejoined the Kentucky House in 1825, and then 1829 to 1832. He appointed and was confirmed as United States district attorney in 1827, but was removed by President Andrew Jackson in 1829; nominated in 1828 by President John Quincy Adams as an Associate Justice of the Supreme Court of the United States, but was not confirmed by the Senate; again elected to the United States Senate as a Whig and served from March 4, 1835, to March 3, 1841. He was appointed Attorney General of the United States by President William Henry Harrison from March to September 1841; appointed and subsequently elected to the United States Senate to fill the vacancy caused by the resignation of Henry Clay and served from March 31, 1842, to June 12, 1848, when he resigned. During this period (27th Congress and 28th Congress) he served on the U.S. Senate Committee on Military Affairs. From 1848 to 1850 he was the Governor of Kentucky and then resigned to again become Attorney General, this time appointed by Millard Fillmore. He served in that position from 1850 to 1853 and then was again elected to the United States Senate and served from March 4 1855, to March 3, 1861. Crittenden was torn by loyalties during the US Civil War, with one son leaving to join the Union and the other enlisting with the Confederate States of America. In December, 1860 he promoted a last minute compromise to hold the Union together, the Crittenden Compromise. It consisted of six unamendable amendments to the Constitution. These amendments would have made permanent the Missouri Compromise of 1820, denied Congress any power to interfere with the interstate slave trade, compelled Congress to compensate owners who lost slaves in the North through illegal interference with the fugitive slave laws, made perpetual the fugitive slave law and three-fifths compromise to the Constitution, and denied to Congress any power to interefere with slavery in the existing Southern states. But Republicans especially president-elect Abraham Lincoln, rejected it and it never came to a vote. Crittenden then tried to salvage his plan by recommending to the full Senate that it be submitted to the people in referendum. It probably would have passed by large majorities in both the North and South, but a majority of the Republicans in the Senate again voted against the measure.

His next compromise the Crittenden-Johnson Resolution was adopted by Congress on July 22, 1861, immediately after the disastrous battle of Bull Run, Congress gave official definition to the object of the war: the war was prosecuted on the part of the federal government not to conquer or subjugate the Southern States, that is, not to reduce them to provinces, nor to interfere with slavery in those states; but to preserve the Union and to defend and maintain the Constitution and the laws, "with all the dignity, equality, and rights of the several states unimpaired, and that as soon as these objects are accomplished the war ought to cease." The resolutions were repealed in December.

He was elected as a Unionist to the 37th Congress (March 4, 1861 - March 3, 1863). He was a candidate for reelection to that office at the time of his death. He died in Frankfort, Kentucky and is interred at the State Cemetery there.

Crittenden had two sons, George Crittenden and Thomas Leonidas Crittenden.