From its organization in July 1861, the Army of the Potomac remained the primary Union military force in the East, confronting General Robert E. Lee's (1807-1870) Army of Northern Virginia in a series of battles and skirmishes. In the early years of the Civil War, however, the Army of the Potomac suffered defeats at the Battle of the First Bull Run in 1861, the Peninsula Campaign and the Battle of Fredericksburg in 1862, as well as the Battle of Chancellorsville in 1863. Historians attribute its initial lack of victories to poor leadership from a succession of indecisive generals: Irvin McDowell (1818-1885), George McClellan (1826-1885), Ambrose Burnside (1824-1881), and Joseph Hooker (1814-1879).

When General George Meade (1815-1872) took command of the Army of the Potomac in June 1863, he was successful in pushing the Army of Northern Virginia out of Pennsylvania following the Battle of Gettysburg. General Ulysses S. Grant's (1822-1885) headquarters were located with Meade's forces for the duration of the War, and he advised Meade to continually attack the Army of Northern Virginia despite heavy casualties among his troops. Though Meade lost large numbers of soldiers at the Battles of the Wilderness, Spotsylvania Court House, and Cold Harbor in 1864, they were ultimately successful in weakening Southern forces and morale, contributing to the Confederate surrender of April 1865. The Army of the Potomac disbanded at the conclusion of the Civil War.