The railroad was formed on June 30, 1889 by the merger of the Cleveland, Columbus, Cincinnati and Indianapolis Railway, the Cincinnati, Indianapolis, St. Louis and Chicago Railway and the Indianapolis and St. Louis Railway. The following year, the company gained control of the former Indiana, Bloomington and Western Railway (through the foreclosed Ohio, Indiana and Western Railway and through an operating agreement with the Peoria and Eastern Railway).
In 1906, the Big Four was acquired by the New York Central Railroad, which operated it as a separate entity until 1922. The Big Four's lines were later incorporated into Penn Central in 1968 with the merger of New York Central and the Pennsylvania Railroad. Penn Central declared bankruptcy in 1970, and in 1976 many of Big Four's lines were included in the government-sponsored Conrail. Conrail was privatized in 1987 and in 1997 was jointly acquired by CSX and Norfolk Southern.