Cave Johnson was born to Thomas and Mary (Noel) Johnson near Springfield, Robertson County, Tennessee on January 11, 1793. He attended Cumberland College in Nashville, Tennessee, studied law, and was admitted to the Bar in 1814. He began practicing law in Clarksville, Tennessee and served as the Prosecuting Attorney of Montgomery County. At this time, he was owner of an iron factory in Clarksville that employed both free and enslaved black people. Johnson supported the continuation of slavery in the U.S., believing it would help the country stay away from secession. By the 1850 census, Johnson had 44 enslaved persons listed on the Slave Schedules, and by 1860, that number had risen to 67.

Johnson was elected to the U.S. House of Representatives as a Jacksonian in 1829, and served in this capacity until 1837. Two years later he was reelected to the House as a Democrat. He continued in this position until 1845. He served as the campaign manager for James K. Polk’s Democratic convention and general election campaigns. After his presidential win, Polk appointed Johnson as Postmaster General of the United States, a position which allowed him to oversee the advent of the modern postal service, including the introduction of the adhesive postage stamp, and dividing mail into classes.

Johnson went on to serve as the Judge of the Seventh Judicial Circuit Court in 1850 and 1851, as President of the Bank of Tennessee from 1854-1860, and as the U.S. Commissioner in settling the affairs of the U.S. and the Paraguay Navigation Company in 1860. During the Civil War, Johnson surrendered Clarksville to Union forces on February 20, 1862. He received a presidential pardon and was elected to the State Senate in 1866. The prevailing forces of the allies of Tennessee Governor William Brownlow, however, refused to allow him to take his seat due to his support of the Confederacy during the Civil War. There are differing accounts of whether Johnson really supported the Union or Confederacy, some reports calling him a "reluctant Confederate” who was “a sound Union man”, and others “heart and soul with the rebels”.

In 1815, Johnson proposed to Elizabeth Dortch, but she decided to marry another man. He vowed to never try proposing again, but by 1838 the now-widowed Elizabeth was ready to accept his proposal, and they had three sons, James, Thomas, and Polk.

Cave Johnson died in Clarksville on November 23, 1866 and is buried in Greenwood Cemetery.