The Burlington and Missouri Railroad came to Red Cloud in 1878. The depot was built in 1897 and was featured in several of Cather's works. Originally located 300 feet southwest of the present location, the depot was moved in 1965 and administered by the Willa Cather Pioneer Memorial and Education Foundation until the Nebraska State Historical Society became the owner in 1978.

Depots in general played a significant role in Willa Cather's writings. The original two-story section of the depot, constructed in 1897, is the building Cather was familiar with during her last years in Red Cloud. On the main line of the Burlington and Missouri between Kansas City and Denver, at one time eight passenger trains passed through town daily, making the Red Cloud Depot a busy and exciting place.

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