Under the directorship of the railway tycoon Cornelius Vanderbilt, the New York Central increased its network throughout the 19th century. The construction of a suspension bridge over Niagara Falls in 1855 by John A Roebling (who later built the Brooklyn Bridge in New York City) gave the railway access to the west via Canadian lines, across southern Ontario. In 1873, its acquisition of the Lake Shore and Michigan Southern gave it a continuous route to Chicago, known, for its easy gradients through the Hudson and Mohawk valleys and along the shores of the Great Lakes, as the ‘water level route’. It promoted this route with the slogan ‘You Can Sleep’ - a reference to the more arduous journey on the Pennsylvania's heavily-graded line over the Allegheny Mountains. After World War II, its passenger services began to suffer, in common with all other US railways, from the competition of the growing interstate highway and airline systems. In 1968 it merged with the Pennsylvania as the Penn Central, but this venture failed, and in 1970 it was taken over by the government's Conrail system. Its New York commuter service is now run by the Metro-North Commuter Railroad.

The small lines across central New York from which the New York Central was created were built to rival the Erie Canal, and had demonstrated the efficiency of rail as an alternative to barge transport. They included the 27 km/17 mi-long Mohawk and Hudson, which ran between Albany and Schenectady and was inaugurated in 1831. The Central originally linked Buffalo and Albany, and connected in the east with two lines running south to New York City - the New York and Harlem (1831; via Chatham) and the Hudson River Railroad (1846; via Hudson, Poughkeepsie, and Peekskill); these later became branches of its system. In the 1850s, it extended its service to St Louis, Missouri. The Central long dominated New York City rail traffic, as the Pennsylvania and Erie railroads and other competitors had to run a ferry service to the city from their termini in New Jersey.