It took its name from the defunct Cleveland, Cincinnati, Chicago and St. Louis Railway, which was nicknamed the "Big Four Railroad".

Kentucky pledged $12 million to replace the deck on the bridge and connect it to the spiral ramp that was completed in Waterfront Park.

The riverboat industry, a big economic factor in Jeffersonville, had requested that the bridge be built further upstream from the Falls of the Ohio, but the United States Army Corps of Engineers approved the building site, even after the vocal protestations.

The first 14 died on January 9, 1890, at 5:40 PM while working on Pier Number 5 foundation when a caisson that was supposed to hold back the river water flooded, drowning the workers.

[6] The Big Four Bridge had one of the biggest bridge disasters in the United States, occurring on December 15, 1893, at 10:20 AM when a construction crane was dislodged by a severe wind, causing the falsework support of a truss to be damaged and the truss—with forty-one workers on it—to fall into the Ohio River.

The accident almost cost more lives, as a ferry crossing the Ohio River just barely missed being hit by the truss.

Also, a new rule was enforced: "never trust a bolted joint any longer than is necessary to put a riveted one in place".

[6] One effect of the opening of the Big Four Bridge was increased transportation of freight by rail, significantly decreasing the number of packet boats that at one time crossed the Ohio River by the dozens.

[7] On February 19, 1904, a Baltimore and Ohio train accidentally crossed the Big Four Bridge, because engineer Dick Foreman fell asleep and went the wrong way at Otisco, Indiana.

On January 14, 1918, two interurbans collided on the Big Four Bridge at 5:30 PM in a blinding snowstorm, killing three passengers (Thomas Alvey, George Greenwald, and Leo Hagan), and injuring 20 aboard.

[12] In 1988 Oscar Arias, President of Costa Rica, contacted Louisville mayor Jerry Abramson to inquire about buying the bridge to dismantle it and reassemble in Costa Rica, as he believed it would be cheaper to import the bridge than build a new one.

From July 26, 1974, to January 1975, both approach spans were removed by the Detzel Construction Company of Cincinnati, Ohio, and were sold for scrap.

Improvements included additional landscaping, a new path west from the ramp, and a plaza underneath the bridge.

[19][20] On May 7, 2008, the bridge caught fire a quarter mile (400 m) north of the Louisville end, shortly after noon, 70 to 80 feet (21 to 24 m) above the Ohio River;[20] suspected to have started from an electrical problem.

The Coast Guard shut down river traffic for about a mile around the bridge due to falling debris.