The 1st Missouri Infantry Regiment evolved from one of several unofficial pro-Unionist Home Guards militia formed in St. Louis in the early months of 1861 by Congressman Francis Preston Blair Jr. and other Unionist activists.

The militia that would become the First Missouri was largely composed of ethnic Germans, although Companies K and I had significant numbers of native born American citizens and Irish-Americans.

Although initially without any official standing, beginning on April 22, 1861, the four "underground" militia regiments Blair helped organize were sworn into Federal service at the St. Louis Arsenal by Captain John Schofield acting on the authority of President Lincoln.

As the Missouri militiamen were being march under guard back to the Arsenal near the riverfront, angry crowds confronted the Federal forces and the confused situation soon devolved into rioting and gunfire.

The resulting Battle of Wilson's Creek fought ten miles south of the city on 10 August 1861, was a bloody affair, and the second costliest in American history up to that time.