The Reading Company main line was extended to Philadelphia, Pennsylvania from Norristown on December 9, 1839.

The Lebanon Valley Branch was opened by the Lebanon Valley Railroad from Reading to Harrisburg, and the line and its railroad were purchased by the Reading Company on March 20, 1858.

The newly created Harrisburg Line continued under Conrail until the late 1990s.

The Harrisburg Line became part of Norfolk Southern Railway on June 1, 1999, after the breakup of Conrail.

At its east end, near the East Falls neighborhood in Philadelphia, the Harrisburg Line junctions with CSX Transportation's Trenton Subdivision and the Philadelphia Subdivision.