Construction began in phases in 1856 under the supervision of Baltimore architect Joseph F. Kemp, who also partly designed the final version, a three-story brick structure with three towers in the Italianate architectural style.

[13] News of the Battle of Fort Sumter, beginning the Civil War, first reached Baltimore on April 12, 1861, at the B&O's Camden Station telegraph office.

[9] The following week, Union troops of the 6th Massachusetts Militia travelling south on the B&O barricaded themselves at Camden Station when they were attacked by Confederate sympathizers in the Baltimore riot of 1861.

[14] Trainloads of wounded soldiers and Confederate POWs came through the station following the Battle of Antietam, 75 miles (121 km) west of Baltimore on September 17, 1862.

A year later, at 10 a.m. on April 21, 1865, the assassinated president's nine-car funeral train arrived at Camden Station, the first stop on its slow journey from Washington to Springfield, Illinois, via the B&O and the Northern Central Railway's Baltimore-Harrisburg, Pennsylvania, line.

The first mainline electrification of a steam railroad in the U.S. occurred at Camden Station on June 27, 1895, when an electric locomotive pulled a Royal Blue train through the Howard Street tunnel.

[17][18] In 1912, the B&O remodeled the central waiting room, enlarging it and adding oak panelling with marble wainscoting for the Democratic National Convention, held in Baltimore that year.

Except for an interval between 1921 and 1935, when the successor Washington, Baltimore and Annapolis Electric Railway (WB&A) used a separate station at Howard and Lombard Streets, frequent electric interurban trains to Maryland's capitol served Camden station until February 5, 1950, when WB&A successor Baltimore and Annapolis Railroad replaced rail passenger service with buses.

[20] The first streamlined, non-articulated diesel locomotive in the U.S., EMC EA-EB #51, began using Camden Station's lower-level platforms in 1937, pulling the B&O's famed Royal Blue.

Today, the lower level tracks and the Howard Street tunnel continue to be extensively used by freight trains of B&O's successor CSX Transportation, as part of its mainline system.

[23] Upgrades included an expanded indoor waiting area, restrooms, new ticketing machines, bike racks, and improved informational displays.