The need for a bridge across the Mississippi at St. Louis to provide a link for eastern and western railroads was discussed as early as 1939. The idea of a bridge was fiercely opposed by the riverboat industry, which regarded bridges as obstacles to navigation, and by the ferrymen, who controlled trans-Mississippi commerce between St. Louis and the cross channel Illinois communities. This opposition and the cost of a bridge made the project unfeasible. The expansion of the railroad systems after the Civil War made a bridge a matter of economic survival for St. Louis if it intended to remain a major link for eastbound and westbound transportation. In 1867 a group of bankers and businessmen formed the St. Louis Bridge and Iron Company and hired Eads to design the bridge.

Eads design set a number of precedents in bridge building. It was the world's first true steel bridge, the first to use tubular cord members, and the first to use cantilever support methods exclusively. It was also the first bridge in the United States to make use of pneumatic caissons in the construction of the piers, which were sunk to unprecedented depths. Eads invented a sand pump to remove gravel, sand, and silt from the caissons so that the sinking operation would continue without interruption. The Eads Bridge was the first large bridge to span the Mississippi River and the first to carry railroad tracks.

The Eads Bridge was constructed over a period of seven years at a cost of over $10,000,000. The bridge consists of three spans and the piers are built of limestone carried down to bedrock. The bridge was dedicated and opened July 4, 1874 with great fanfare. After a 100-gun salute and a parade 14 miles long that wound through the streets of St. Louis’ streets 150,000 people looked on as General William Tecumseh Sherman drove the last spike. An enormous fireworks display followed later that evening.

At the time it was built the Eads Bridge was the world’s largest bridge with an overall length of 6,442 feet. The upper deck extended over the entire width with a vehicular roadway and two pedestrian walkways. After a tornado crumpled the superstructure of the east abutment in 1871, the bridge was redesigned to be tornado proof and survived being struck again by a tornado in 1896. The East St. Louis & Suburban Railway Co. opened electric railway in 1896 between East St. Louis and St. Louis over the Eads Bridge. This service continued until 1935. In 1947, this deck was replaced with concrete filled "I Beam Lok" and the roadway was widened.

The Eads Bridge was dedicated as a National Historic Landmark in 1964. The last train passed over the bridge in 1974 and the bridge was closed to automobile traffic in 1991 due to deterioration of the deck supports. The bridge was reopened to rail traffic when the first phase of MetroLink opened in 1993. A restoration project initiated by the City of St. Louis was completed in 2003 when the bridge was reopened to automobile traffic. Today the Eads Bridge supports automobile, MetroLink, bicycle and pedestrian traffic. The bridge can also be closed to automobile traffic and used as the site for various festivals and celebrations.