The Ohio and Pennsylvania Railroad opened the line from Allegheny west to Crestline in 1851, 1852, and 1853; the Fort Wayne Railroad Bridge connected it to the Pennsylvania Railroad's Main Line in downtown Pittsburgh in 1857. From Crestline west to Fort Wayne, the Ohio and Indiana Railroad opened the line in 1853 and 1854. The Fort Wayne and Chicago Railroad extended the line west to Columbia City in 1856, on July 26 the three companies merged to form the Pittsburgh, Fort Wayne and Chicago Rail Road. The line was completed to Chicago in 1856 and 1858. The Pennsylvania Railroad began operating the line under lease on July 1, 1869. The line was subleased to the Pennsylvania Company on April 1, 1871, which operated it until January 1, 1918, when the lease was reassigned to the PRR. It passed to Penn Central Transportation in 1968 and Conrail in 1976. The line from Fort Wayne east to Alliance was not as favored in the Conrail system as the duplicate New York Central lines, and during rationalization efforts that took place in the early 1980s, this section of the Fort Wayne line changed in importance. Traffic heading from Pittsburgh to Chicago was routed onto the Cleveland Line at Alliance, while traffic towards Columbus, Cincinnati, Indianapolis and St. Louis was routed onto the former New York Central Big Four line at Crestline. The remainder of the line west of Crestline was reduced to a single track with passing sidings. The route's automatic block signals were downgraded to an absolute permissive block system with home signals at passing sidings and diamonds. This route was used by Amtrak's Capitol Limited until the early 1990s, when the train was rerouted via the CSX Chicago line and then eventually rerouted again onto the eastern half of the Fort Wayne line to Alliance. After the end of Amtrak service on the western end of the Fort Wayne line, all intermediate signals west of Crestline were taken out of service, and the route transitioned into being run by track warrant control. Conrail built a RoadRailer facility just west of Crestline, taking advantage of the light traffic on the Fort Wayne line, and Crestline's proximity to U.S. Routes 23 and 30. This facility was closed during the Conrail split. After the breakup of Conrail in 1999, CSX acquired Conrail's portion of the line from Crestline to Fort Wayne and NS's portion of the line west of Fort Wayne, giving CSX a second route to Chicago. NS kept trackage rights and acquired the line east of Crestline. The decision to give CSX the Fort Wayne line west of Crestline required the construction of a new interchange track in the northwest corner of the crossing with the Big Four line that CSX acquired. As part of the trackage rights agreement, Norfolk Southern is allowed to run up to 8 trains per day between Crestline and Bucyrus, where they have connections to their former N&W mainline from Sandusky to Portsmouth, and up to 6 trains a day into Fort Wayne. Norfolk Southern utilized their trackage rights heavily during the first year or so after the Conrail split, however as infrastructure improved on the former New York Central and former Nickel Plate Road Chicago lines, the need for trackage rights decreased. In 2014 however, Norfolk Southern has begun running low priority extra segments of regularly scheduled trains via the western end of the Fort Wayne line to alleviate congestion on the very busy former New York Central Chicago line.
