Fredericksburg sits on the banks of the Rappahannock, at the head of river navigation, which has made it an important site since colonial times. The Virginia General Assembly established a fort in the area in 1676, just south of the present city. In 1720, the Assembly established a new county, Spotsylvania (after the governor) and established Fredericksburg in 1728 as a river port for the 18-century settlers. Named for Frederick, Prince of Wales, son of George II, the streets bore names of the royal family.

For a time, it served as the county seat, and was later incorporated in 1781. It received its charter as an independent city in 1879. The city is closely associated with George Washington, whose family moved in 1738 to a farm in Stafford County, across the Rappahannock from Fredericksburg, so that Augustine Washington could live closer to the Accokeek Creek Iron Furnace, which he managed. The house—uncovered finally in an archaeological dig in July 2008—was central to the Washington family from the 1740s until 1772, when Mary Washington moved across the river to Fredericksburg.

Rail service has been important in Fredericksburg since the Richmond, Fredericksburg and Potomac Railroad was chartered in 1834 to run a line from Richmond up to the Potomac River at Aquia Creek. The original Fredericksburg train station was a ground-level stationhouse, and the area adjacent to the tracks was once Fredericksburg’s industrial and commercial corridor.

Throughout the Civil War, control of the railroad through Fredericksburg was of strategic importance due to its position midway between Washington, D.C. and Richmond, Virginia, the opposing capitals.

During the Battle of Fredericksburg in early December of 1862, the town sustained significant damage due to bombardment and looting at the hands of Federal troops, who were in turn devastated at Confederate hands.

A second battle was fought in and around the town in connection with the Chancellorsville Campaign in 1863; and the Battle of the Wilderness and the Battle of Spotsylvania Court House were fought nearby in May 1864. The extensive nearby battlefield parks, the Fredericksburg and Spotsylvania County Battlefields Memorial, pay tribute to what has been called the bloodiest landscape in the country, vividly reflect the Civil War's terrible cost—more than 85,000 men wounded and 15,000 killed—and honor the trials of a community and nation at war. After the war, Fredericksburg recovered its position as a center of local trade and expanded. By 1872, rail connections went through to Washington, D.C., giving this portion of Virginia an all-rail route from Richmond and across the Potomac to Washington.

The University of Mary Washington was founded in Fredericksburg in 1908 as a women's school, and evolved under the University of Virginia system into an independent coeducational institution. Concerned about rapid and safe transport of goods during World War I, the Federal Government established the Railway Express Agency (REA) in 1917 to utilize existing railroad for small package and parcel transit. The REA expanded rapidly with small offices across the country, and with railroads as a catalyst for then-modern concepts like standardization of time through time zones and accelerated delivery, many came to depend on the REA for their shipping needs.

The Fredericksburg REA office was constructed around 1927, replacing a two-story wood frame American Railway Express Depot structure and taking on an odd shape as a result of a spur line that branched off the main rail line. Fredericksburg’s REA office, or better known as the “Railway Express Depot,” used the nearby RF&P tracks until REA dissolved in 1975.

The “Fredericksburg Railway Express Depot” is one in a series of railroad buildings that represents an era of unprecedented national interconnection. The RF&P railroad company buildings in Fredericksburg – both the passenger and large freight station constructed in 1910 – included architectural detailing reflecting the prosperity and dominance of the railroad in the national economy. The Railway Express Depot, however, was more utilitarian and traditional for a train/warehouse district, although the building exhibits excellent brickwork. The exterior of the building remains relatively unchanged, and the interior has been renovated within the city’s historical guidelines.

The Railway Express Depot is recognized as a contributing building to the Fredericksburg Historic District. The Fredericksburg Historic District is listed on both the Virginia Landmarks Register and the National Register of Historic Places.

Fredericksburg has been home to many notables other than the Washington family, including George Mason, John Paul Jones, George Wheedon, and Hugh Mercer; and in modern times, actor Judge Rheinhold and author Florence King.

Today, Fredericksburg is the hub of a rapidly growing region in Northern Virginia; however, it still retains its 40-block historic district. For example, one block from the Rappahanock River waterfront, sits the 1910 brick railroad station structure built by the RF&P, which has most recently been occupied by the german restaurant, Bavarian Chef. This, along with the surrounding memorial battlefield monuments has lead Fredericksburg to be aptly nicknamed, “America's most historic city.” RF&P was succeeded by CSX after the RF&P ceased operating in 1991.