[2] With a border formed by the Missouri River, the county was organized November 25, 1820, and named for Captain James Callaway, grandson of Daniel Boone.

[3] The county has been historically referred to as "The Kingdom of Callaway" after an incident in which some residents confronted Union troops during the U.S. Civil War.

Among the first mentioned in county histories are those around the southeastern Callaway settlement of Heilburn, a community neighboring Portland, on the Missouri River.

Some of them brought black slaves and enslavement practices with them, and quickly started cultivating hemp and tobacco, the same crops as were grown in Middle Tennessee and Kentucky.

[9][10] Some pioneer families from Callaway and Lewis County, Missouri, moved to the West and became influential early settlers of the nascent state of California.

Lewis County relatives helped build Sacramento and develop viticulture in the California Central Valley and areas north of San Francisco Bay.

Some of these Missouri families, later key U.S./Unionist advocates and military personnel during the U.S. Civil War, held early local and statewide political offices in California.

A truce with U.S./Union forces during the war effectively allowed Confederate advocates to continue to operate under surveillance, in proximity to the Missouri government offices in Jefferson City.

Violence against Black people reached a peak around the turn of the 20th century, when whites lynched a total of four African Americans in the county.

[9][17] Other settlers in the Missouri River valley included German immigrants from the mid-19th century following the Revolutions of 1848 in the German states; they established a strong wine industry in the area and built towns with German-influenced architecture, concentrated substantially in counties south of Callaway and across the Missouri River, celebrated annually in the Maifest events in the Gasconade county seat, Hermann.

The most predominant denominations among residents in Callaway County who adhere to a religion are Southern Baptists (41.60%), Roman Catholics (14.00%), and United Methodists (9.41%).

Callaway County, along with the rest of the state of Missouri, is represented in the U.S. Senate by Josh Hawley (R-Columbia) and Roy Blunt (R-Strafford).

Like most rural areas throughout Missouri, voters in Callaway County generally adhere to socially and culturally conservative principles which tend to influence their Republican leanings.

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

Incumbent President Donald Trump (R-Florida) faced a primary challenge from former Massachusetts Governor Bill Weld, but won both Callaway 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 in Callaway County.

On the Democratic side, former Secretary of State Hillary Clinton (D-New York) narrowly won statewide, but Senator Bernie Sanders (I-Vermont) carried a majority of the vote in Callaway County.

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).

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

Then-Senator Hillary Clinton (D-New York) received more votes than any candidate from either party in Callaway County during the 2008 presidential primary.

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