During the lead-up to the American Civil War, the proposed secession of Missouri from the Union was controversial because of the state's disputed status. The Missouri state convention voted in March 1861, by 98-1, against secession, and was a border state until abolishing slavery in January 1865. Missouri was claimed by both the Union and the Confederacy, had two rival state governments, (its Confederate state “government” in exile, operating out of northern Texas), and sent representatives to both the United States Congress and the Confederate Congress.

Despite sporadic threats from pro-Confederate irregular armies and the Confederacy controlling Southern Missouri early in the war, the Union government had established permanent control of Missouri by 1862, with the Missouri Confederate government functioning only as a government in exile for the rest of the duration of the war after being driven from the state.

In the aftermath of the 1860 election, the governor of Missouri was Claiborne Fox Jackson, a Southern sympathizer who favored secession. At his inauguration, during the so called Secession Winter Jackson had requested the authorization of a state constitutional convention to consider the relationship between Missouri and the Federal government. A special referendum approved the Missouri Constitutional Convention and delegates were elected. Contrary to Jackson's expectations, no avowed secessionist delegates were elected. In February, Jackson unsuccessfully argued for Missouri's secession before the State Constitutional Convention convened to debate the issue under the leadership of former governor Sterling Price. Most of Missouri, like Price, held "conditional Unionist" beliefs at this point, meaning they neither favored secession nor supported the United States warring against the Confederacy. They voted against secession on March 19, 1861.^{[citation needed]}

In early February, United States Army Captain Nathaniel Lyon, was transferred to Missouri and stationed at the St. Louis Arsenal. The arsenal was under the command of Brevet Major Peter V. Hagner and supervised by Brigadier General William S. Harney, commander of the U.S. Army's Department of the West. Both men were considered moderates on the issues of slavery and sectional conflict by pro-slavery and southern sympathizer President James Buchanan's administration. Both men believed a policy of appeasement would keep Missouri in the Union, with Harney in particular having deep ties to the Missouri elite through his wife's family. Lyon on the other hand believed conflict was inevitable in Missouri, and that appeasement was a dangerous mistake. He came to this position from his experience with the violence carried out by Missouri "border-ruffians" during Bleeding Kansas.

The St. Louis Arsenal, containing one of the largest caches of military supplies in the West, was of great strategic importance to any coming conflict in the state. During the Secession Winter a number of Southern States seceded from the Union. In addition, these states began to seize Federal military instillations within their borders, taking the arms and artillery held within them. While Missouri voted not to secede, many in the state were pro-secession and Lyon feared that the Arsenal was too poorly defended to resist an attempt to take it if one was made. Seeking to increase the number of Union troops who could be called on to defend the Arsenal, in early March of 1861 Lyon began to train and help arm a Pro-Union militia in secret. This militia was mostly made up of anti-slavery German immigrants and pro-republican members of the St. Louis chapter of the Wide Awakes. Lyon was supported by Congressman Frank Blair, an ally of Abraham Lincoln, with powerful connections to the incoming president through his brother Montgomery Blair.

After Lincoln called for Union troops in preparation for the Civil War, Lyon recognized an opportunity to strengthen the Arsenal garrison by mustering the pro-Union militia into the Federal army. Up until that point, the militia had limited arms, consisting only of what they successfully smuggled into Missouri from Illinois. As of late March, however, Hagner still supervised the arsenal and Harney still commanded the Department of the West. Neither Hagner nor Harney were supportive of Lyon's plans with the militia, and Hagner denied Lyon's attempts to release the arsenal's weapons to them. After this denial Lyon began exerting pressure on the president through the politically connected Blair to have himself named the new commander of the arsenal.

Blair promptly did so and, as the Battle of Fort Sumter began almost simultaneously, orders where sent to Harney to organize Federal militia in Missouri. After failing to act on these orders, and facing criticism from Blair, Harney was ordered by War Department to return to Washington by Simon Cameron. On April 21, 1861, with Lyon's control of the arsenal now unimpeded, he armed the militia at night and ordered them to take the rest of the Arsenal's weapons up river to Illinois. He did this in response to the seizure of the smaller Liberty Arsenal by pro-secession members of the Missouri State Militia the day before. Finally, on April 23 with the pro-Union militia armed and the guns safe, Lyon formally mustered the troops into the Federal Army.

At the same time, Governor Claiborne Fox Jackson began conspiring with the newly declared Confederacy to have arms and artillery given to pro-Confederate forces in the Missouri State Militia. Ordering the State Militia to begin mobilizing on May 1, an encampment was established outside of St. Louis called Camp Jackson. While the Governor claimed that this was only a training exercise, on May 9, the Confederate equipment was delivered to the camp to help them take the Arsenal by force.