In 1865, the Philadelphia and Baltimore Central Railroad began building a line from Oxford, Pennsylvania to Rising Sun, Maryland in a attempt to take passengers from the Philadelphia area to smaller rural towns south of the city. The line reached Rising Sun, MD, in 1868 and with the demand for freight out of Baltimore, The P&BC continued the line to the Columbia and Port Deposit (C&PD) Railroad line (which ran from Perryville, Marland to Harrisburg, Pennsylvania) at Octoraro. The connection of the two lines marked a turning point in the history of the towns that lined the right-of-way.

Between 1880 and 1881, The P&BC owned and operated the line but because of the recent merger of the Philadelphia, Baltimore and Washington Railroad and the C&PD, new leasing was needed to get freight traffic to Baltimore, MD. This sparked a new alliance between the PB&W and the P&BC. The two railroads eventually merged into one until 1916, running under the PB&W name. On October 2nd, 1916, The line was bought by the succesor of the PB&W, the Philadelphia, Wilmington and Baltimore Railroad.

Everything from 1916 to 1920 was going good for the railroad until a new highway was built between Conowingo, MD and Kennett Square, PA. This new highway was built parallel to the railroad and saw heavy traffic compared to the failing Octoraro Branch. Given that the Great Depression would hit within the next decade, the line's future was not bright and in 1935, passenger service permanetly ended on the line. From 1916 to 1961, The Pennsylvania Railroad took over the PW&B and used this line for freight until 1961, at which time the line was shortened to Colora, Maryland.

Today, the active portion of the Octoraro Branch is operated to Nottingham, PA by the East Penn Railway, a shortline operating on the former line hauling grain, oil and potato chips. Before East Penn Railways took over, the line was operated under the Octoraro Railroad, between 1980 and 1994, then the Morristown and Erie Railroad up until 2004 when East Penn Railways assumed control.

See also the eastern end of this entire right-of-way, The Chester Creek Branch, which is also abandoned.