It replaced a downtown Santa Fe complex that included a 1910 depot, Railway Express Agency (REA) building, and freight office.

[4] On December 15, 2021, Amtrak moved its operations back to the historic Santa Fe Depot, located directly in downtown Fort Madison.

The city, in collaboration with BNSF, Amtrak, the Iowa Department of Transportation, the Southeast Iowa Regional Planning Commission, and the North Lee County Historical Society (NLCHS), has worked since 2006 to restore the old Santa Fe station to accommodate an Amtrak waiting room and ticket office as well as exhibition and storage space for the NLCHS museum, which moved into the old depot in 1972.

Eventually, the city decided to sponsor a project to lift the depot off of its foundation, construct a new five foot high concrete base, and lower the building back into place; this work occurred during 2011.

[4] Once the renovation was completed, Amtrak moved the Fort Madison stop to the depot, which also continues to house the NLCHS museum.