The county was organized November 16, 1820, removed from the former larger Howard County (now to the northwest) of the old federal Missouri Territory of 1812-1821, and named for the famous Western explorer and settler of Kentucky, then recently deceased Daniel Boone (1734-1820), whose kin largely populated the Boonslick area, having arrived in the 1810s on the Boone's Lick Road.

Boone County was settled primarily from the Upper South states of Kentucky, Tennessee and further east of Virginia.

The settlers brought slaves and idea of slave-holding with them, and quickly started cultivating crops similar to those in Middle Tennessee and the bluegrass state of Kentucky: hemp and tobacco.

Boone was one of several counties to the north and south of the diagonal flowing southwestward Missouri River that was settled by mostly Southerners.

They also directed that all public buildings including the county courthouse and the nearby state university be draped in black mourning for thirty days.

As a county anchored by a college town, Boone holds a Democratic tendency at the local, state, and federal levels.

On October 27, 2021, Alford Sr. announced his candidacy for the United States House of Representatives in Missouri's 4th congressional district as a Republican in the 2022 elections.

[19] Boone County, along with the rest of the state of Missouri, is represented in the U.S. Senate by Josh Hawley (R-Columbia) and Eric Schmitt (R-Glendale).

On the Democratic side, former Vice President Joe Biden (D-Delaware) both won statewide by a wide margin and carried a majority in Boone County.

Incumbent President Donald Trump (R-Florida) faced a primary challenge from former Massachusetts Governor Bill Weld, but won both Boone County and statewide by overwhelming margins.

Businessman Donald Trump (R-New York) narrowly won the state overall, but Senator Ted Cruz (R-Texas) carried a plurality of the vote in Boone County.

The 2012 Missouri Republican Presidential Primary's results were nonbinding on the state's national convention delegates.

Senator Rick Santorum (R-Pennsylvania), who finished first in the state at large, but eventually lost the nomination to former Governor Mitt Romney (R-Massachusetts).

Incumbent President Barack Obama easily won the Missouri Democratic Primary and renomination.

In 2008, the Missouri Republican Presidential Primary was closely contested, with Senator John McCain (R-Arizona) prevailing and eventually winning the nomination.

Then-Senator Barack Obama (D-Illinois) received more votes than any candidate from either party in Boone County during the 2008 presidential primary.

Despite initial reports that Hillary Clinton (D-New York), also a senator at the time, had won Missouri, Obama narrowly defeated her statewide and later became that year's Democratic nominee, going on to win the presidency.

This changed after an elderly handicapped woman died in a house fire just west of the city limits of Columbia.