At the north border of Central Park is the final stop on the line, Central Park North – 110th Street. From there the line curves southwest and west under Central Park (one of three lines to do so, the other two being the IND 63rd Street Line and the BMT 63rd Street Line), and heads west under 104th Street. The line turns southwest and south to run underneath the IRT Broadway – Seventh Avenue Line, passing under part of the northbound platform at 103rd Street. After the center express track on the Broadway – Seventh Avenue Line ends by connecting to the two local tracks, the Lenox Avenue Line rises to become the two express tracks, with double crossovers to each local direction. The four-track Broadway – Seventh Avenue line then continues south through 96th Street, an express station and transfer point.
The line opened south of 145th Street just after midnight on November 23, 1904, as part of the IRT's original system. It was known as the East Side Subway or East Side Branch at the time, as it was the spur of the main line to the east side. The first train ran from the line onto the IRT White Plains Road Line (known as the West Farms Branch or the West Farms Extension) just after midnight on July 10, 1905. Soon after the line opened, it was speculated that it would bring prosperity to Harlem.
The Harlem – 148th Street station was opened on May 13, 1968 on land that had been part of the Lenox Yard; the station was originally called Lenox Terminal–148th Street.
The line has always carried trains of two service patterns, currently designated 2 and 3; see those articles for details. Prior to the 1950s, 1 locals used this line switching to the local at 96th Street.
From March to October 1998, the tunnel that carried the 2 and 3 services had very limited service, and was reconstructed along with the cracked invert (tunnel floor) repaired, correcting a major water problem that existed in this area for many years due to many underground streams located around the Lenox Avenue area that caused extensive water damage, and water seepage problems, causing many extensive and severe delays due to constant track and roadbed flooding. Many 2 trains were rerouted via the IRT Lexington Avenue Line, while the 3 trains were rerouted to the 137th Street on the IRT Broadway – Seventh Avenue Line. Supplemental shuttle bus service connecting to other lines in the area were provided at this time. 
From 1995 until 2008, the line's two northernmost stations, Harlem – 148th Street and 145th Street, were served by shuttle buses during the late-night hours. Full-time service was restored on July 27, 2008.
Note that this is a list of New York City Subway lines, which are the physical infrastructure over which services operate.
Lines with colors next to them are trunk lines; trunk lines determine the color of New York City Subway service bullets, except for shuttles, which are dark gray.