In 1853, plans were made for the railroad in this area to run through Dover to the north of Russellville. However, upon construction in 1873 by the Little Rock/Fort Smith Railroad, it ultimately ran through Russellville.

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The original depot was constructed in 1880 as a frame structure and noted in a newspaper article as "the largest on the Little Rock and Fort Smith road outside of Little Rock" (September 23, 1880). Between 1873 and 1910, the railroad brought much business and population growth to Russellville, which helped make it the town it is today.

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Construction of the current Missouri-Pacific depot began in 1916 and was completed in February 1917. In 1918, it was used as a departure point for troops heading into service during World War I. The last passenger train to leave the Russellville Depot was Southbound Train #125, which departed at 9:01pm on March 28, 1960. After a transition to Union Pacific, the depot continued railroad freight and maintenance functions until 1999 when it was acquired by the city and rehabilitated under the guidance of Main Street Russellville and Friends of the Depot.

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The building is currently the home of the Main Street Russellville office and is available for private rental.