On July 26, 1856, the Pittsburgh, Fort Wayne and Chicago Rail Road was formed as a consolidation of the Fort Wayne and Chicago, Ohio and Indiana, and Ohio and Pennsylvania Railroads. Extensions opened west to Warsaw September 28, Plymouth November 10, Englewood, Illinois (south of Chicago) on November 29, 1858, and Van Buren Street in Chicago on December 25, 1858. On January 1, 1859, trains started running to Chicago, with a terminal at the future location of Union Station. The part west of Plymouth was built with rails removed from the New Portage Railroad.
From the early days, the Pennsylvania Railroad (PRR) had been involved with the project, supplying funds. Once the Fort Wayne Railroad Bridge at Pittsburgh was finished in 1857, trains began to run through from Philadelphia. In 1858 the PFW&C began using the first Union Station in Pittsburgh, shared with the PRR.
On July 1, 1859, the PFW&C defaulted on its debts, and was sold at foreclosure on October 24, 1861. It was reorganized as the Pittsburgh, Fort Wayne and Chicago Railway February 26, 1862.
On July 1, 1865, the PFW&C leased the New Castle and Beaver Valley Railroad, giving it a branch from Homewood, Pennsylvania north to New Castle. The Lawrence Railroad, branching west from Lawrence Junction on the NC&BV to Youngstown, Ohio, was leased on June 27, 1869. On June 1, 1887, the Lawrence Railroad became part of the Youngstown, Lawrence and Pittsburgh Railroad, which on August 1 merged into the PRR's Pittsburgh, Youngstown and Ashtabula Railroad, and on January 9, 1906, that merged with the New Castle and Beaver Valley to form the Pittsburgh, Youngstown and Ashtabula Railway, still leased to the PRR.
The PFW&C bought the Cleveland, Zanesville and Cincinnati Railroad by deed on July 1, 1865, making it its Akron Branch. The line ran from Hudson, Ohio, on the Cleveland and Pittsburgh Railroad south through Akron, crossing the PFW&C at Orrville and continuing to Millersburg. In 1868 a short 3.5 mile (5.5 km) extension to the south was built, and on November 4, 1869, the PFW&C sold the line to the Pittsburgh, Mt. Vernon, Columbus and London Railroad. That company later became part of the PRR's Cleveland, Akron and Cincinnati Railway.
On May 22, 1869, the PFW&C leased the Massillon and Cleveland Railroad, giving it a short branch from Massillon north to the Akron Branch at Clinton.
On July 1, 1869, the PRR leased the PFW&C and began operating it directly, but on April 1, 1871, the PFW&C was transferred to the newly formed Pennsylvania Company. On December 1, 1871, the Pennsylvania Company leased the Cleveland and Pittsburgh Railroad. Since January 25, 1860, the C&P had been operated jointly by itself and by the PFW&C, providing a branch of the PFW&C from Rochester, Pennsylvania, west and north, crossing the PFW&C at Alliance, Ohio, and continuing to Cleveland.
Operation was transferred back to the Pennsylvania Railroad from the Pennsylvania Company on January 1, 1918.