The coming of the Northern Pacific Railway to Missoula ensured the town's economic prosperity as a major transportation hub in Western Montana.

The current depot, which was completed in 1901, was designed by architects Reed and Stem of St. Paul, Minnesota, in a simplified Renaissance Revival style of architecture.

[2] Reed and Stem designed over 100 railroad depots, including the Grand Central Terminal in New York City.

[2][4][5] The depot is constructed of beige Roman brick that had been salvaged by Northern Pacific from the railroad's abandoned Olympian Hotel project in Tacoma, Washington, that would later be rebuilt as Stadium High School.

[2] The Missoula depot features a main three-story structure flanked by one story wings on each side.