William Quantrill was born at Canal Dover, Ohio on July 31, 1837. His father was Thomas Henry Quantrill, formerly of Hagerstown, Maryland, and his mother, Caroline Cornelia Clark, was a native of Chambersburg, Pennsylvania. Quantrill was also the oldest of twelve children, four of whom died in infancy. By the time he was sixteen, Quantrill was teaching school in Ohio. In 1854, his abusive father died of tuberculosis, leaving the family with a huge financial debt. Quantrill's mother had to turn her home into a boarding house in order to survive. During this time, Quantrill helped support the family by continuing to work as a schoolteacher, but he left home a year later and headed to Mendota, Illinois. Here, Quantrill took up a job in the lumberyards, unloading timber from rail cars.
One night while working the late shift, he killed a man. Authorities briefly arrested him, but Quantrill claimed that he had acted in self-defense. Since there were no eyewitnesses and the victim was a stranger who knew no one in town, William was set free. Nevertheless, the police strongly urged him to leave Mendota. Quantrill continued his career as a teacher, moving to Fort Wayne, Indiana in February 1856. The district was impressed with Quantrill's teaching abilities, but the wages remained meager. Quantrill journeyed back home to Canal Dover that fall, with no more money in his pockets than when he had left.
Quantrill spent the winter in his family's diminutive shack in the impoverished town, and he soon grew rather restless. At this time, many Ohioans were migrating to the Kansas Territory in search of cheap land and opportunity. This included Henry Torrey and Harmon Beeson, two local men hoping to build a large farm for their families out west. Although they didn't trust the 19-year-old William, Bill's mother's pleadings persuaded them to let her son accompany them in an effort to get him to turn his life around. The party of three departed in late February 1857. Torrey and Beeson agreed to pay for Quantrill's land in exchange for a couple of months' worth of work. They settled at Marais des Cygnes, but things did not go as well as planned. After about two months, Quantrill began to slack off when it came to working the land, and he spent most days wandering aimlessly about the wilderness with a rifle. A dispute arose over the claim, and he went to court with Torrey and Beeson. The court awarded the men what was owed to them, but Quantrill only paid half of what the court had mandated. While his relationship with Beeson was never the same, Quantrill nevertheless remained friends with Torrey.
Shortly afterwards, Quantrill accompanied a large group of hometown friends in their quest to start a settlement on Tuscarora Lake. But soon neighbors began to notice Bill stealing goods out of other people's cabins, so they banished him from the community in January 1858. Soon thereafter, he signed on as a teamster with the U.S. Army expedition heading to Salt Lake City, Utah in the spring of 1858. Little is known of Quantrill's journey out west, except that he excelled at the game of poker. He racked up piles of winnings by playing the game against his comrades at Fort Bridger but flushed it all on one hand the next day, leaving him dead broke. Quantrill then joined a group of Missouri ruffians and became somewhat of a drifter. The group helped protect Missouri farmers from the Jayhawkers for pay and slept wherever they could find lodging. Quantrill traveled back to Utah and then to Colorado, but returned in less than a year to Lawrence, Kansas, in 1859  where he taught at a schoolhouse until it closed in 1860. He then took up with brigands and turned to cattle rustling and anything else that could earn him money. He also learned the profitability of capturing runaway slaves and devised plans to use free black men as bait for runaway slaves, whom he subsequently captured and returned to their masters in exchange for reward money .
Initially, before 1860, Quantrill appeared to support the anti-slavery side. For instance, he wrote to his good friend W.W. Scott in January 1858 that the Lecompton Constitution was a "swindle" and that James H. Lane, a Northern sympathizer, was "as good a man as we have here." He also called the Democrats "the worst men we have for they are all rascals, for no one can be a democrat here without being one." However, in February 1860, Quantrill wrote a letter to his mother expressing his views on the anti-slavery supporters. He told her the pro-slavery movement was right and that he now detested Jim Lane. He said that the hanging of John Brown had been too good for him and that, "the devil has got unlimited sway over this territory, and will hold it until we have a better set of man and society generally."