Before Lawrence even existed these rolling plains were home to Native Americans for thousands of years. The Kanza, Osage, Wichita, Kiowa, Kiowa-Apache, Comanche, Pawnee, Cheyenne and Arapaho were the most prominent indigenous nations in the area.

But, as the new America began to push West in the 1820s, traders and explorers started to travel the western  trails of what would become known as the Oregon and Santa Fe Trails. These paths had long been used by the Indians between camping and hunting sites. Explorers, trappers, traders, soldiers and settlers began to follow the Indian paths to the West with earnest. The settlement of Lawrence, which would not be formed for another thirty years, was located between the Oregon and Santa Fe Trails.

The Kansas Territory was opened to settlement on May 30, 1854 by the Kansas-Nebraska Act. According to the concept of "popular sovereignty," settlers could decide whether to admit their territory as a slave or free state. Soon, New England abolitionists began organizing emigrant aid societies to encourage like-minded citizens to settle in the new territory. On August 1, 1854, Twenty-nine northern emigrants, mostly from Massachusetts and Vermont, were the first to arrive in Lawrence, Kansas, named for Amos A. Lawrence, a promoter of the Emigrant Aid Society. A second party of 200 men, women and children arrived in September. Lawrence is one of the few cities in Kansas founded purely for political reasons.

On October 16, 1854, the first anti-slavery newspaper was established in Lawrence to voice the sentiments of the New England Emigrant Society. The newspaper, called the Kansas Pioneer, enraged the pro-slavery supporters. The name of the paper shortly changed to the Kansas Tribune.

The first school taught in Lawrence was commenced January 16, 1855, by Edward P. Fitch, who came from Hopkinton, Massachusetts. Located in the back office of the Emigrant Aid Building began with about twenty students.

On December 1, 1855, a small army of Missourians, acting under the command of "Sheriff" Samuel J. Jones, laid siege to Lawrence in the opening stages of what would later become known as "The Wakarusa War." However, the intervention of the new governor, Wilson Shannon, kept the proslavery men from attacking Lawrence.

But, later when a young man, who had come to the aid of the Free-Staters, rode off to his home about six miles west of Lawrence, he was met on the way by a group of pro-slavery men from Lecompton. Though the man never even drew his weapon, he was shot in cold blood by the pro-slavery faction. His body was returned to Lawrence where the entire citizenry followed it to its burial, in the presence of his young wife and children, in Pioneer Cemetery. This event, more than any other, hardened the Free-Staters to the realization that they had come, not simply for an election to determine whether Kansas would be free or slave, but to fight a war over the issue.