Osawatomie's name is a compound of two primary Native American tribes from the area, the Osage and Pottawatomie.

Settled by abolitionists in hope of aiding Kansas's entry to the United States as a free state, the community of Osawatomie and pro-slavery communities nearby was quickly the targets of violence by pro-enslavement forces such as Border Ruffians.

[8] In March 1855, abolitionists Reverend Samuel Adair and his wife Florella settled in a cabin near Osawatomie to serve as missionaries to the community.

Florella's half-brother, John Brown came to Bleeding Kansas later the same year with a wagon of guns in order to help fight the pro slavery forces like his five sons, who were already living in another community in the area.

By 1856, having established himself as a leader of free state guerillas, Brown made Osawatomie and the Adair cabin his base.

In a raid in May 1856, Brown killed five pro-slavery men along Pottawatomie Creek near the current town of Lane, Kansas.

Osawatomie played a key role throughout the Civil War, serving as a center for Jayhawker activity.

[10] In recognition for Osawatomie's part in ensuring Kansas remained a free state, the Kansas Legislature established the Osawatomie State Mental Hospital in 1863, the first mental hospital west of the Mississippi River.

[8] By 1879, a railroad was built to serve Osawatomie, aiding its growth into a supply town and a main shipping point.

A pro-slavery force of 250, led by John William Reid, came riding into Osawatomie from another direction.

When Reverend Adair heard the shot, he sent his own son to warn and notify John Brown of the raid.

However, despite the attempts of Brown to get Reid's men to follow, they instead looted and burned Osawatomie.

[9] On August 31, 1910, President Theodore Roosevelt gave his famous New Nationalism speech in Osawatomie.

The central issue he argued was government protection of human welfare and property rights.

[11][12] On December 6, 2011, President Barack Obama gave an economic speech reprising many of Roosevelt's themes at Osawatomie High School.

[15] The climate in this area is characterized by hot, humid summers and generally mild to cool dry winters.

The Karl E. Cole Sports Complex in Osawatomie is used for athletic events such as baseball, softball, soccer, and youth football.

[8] Osawatomie hosts the John Brown Jamboree, an annual arts, crafts, and music festival each summer.

Each October, the Talking Tombstones event is held at Oakwood Cemetery, with reenactments of historical figures buried there, to remember their lives and contribution to the community's history.