Major cities on the route include Poughkeepsie, Albany, Schenectady, Amsterdam, Utica, Syracuse, Rochester, and Buffalo.

The Amtrak-owned section between 41st Street and the merge with the Hudson Line is unpowered, and can only be served by diesel or dual-mode trains.

[3] Amtrak owns trackage rights for most of the Hudson line section north of Poughkeepsie to its rail yard in Albany.

South of Poughkeepsie, the Empire Corridor is coextensive with Metro-North's trackage until it forks-off between Metro-North's Riverdale and Spuyten Duyvil stations in the Bronx, to cross the Harlem River over the Spuyten Duyvil Bridge and make the Empire Connection to Penn Station.

The corridor had been part of the main line of the New York Central Railroad; it was the eastern leg of the NYC's famed "Water Level Route" to Chicago.