He took part in studies of possible transcontinental railroad routes, creating the first comprehensive map of the United States west of the Mississippi in 1857. This required extensive explorations of the vast Nebraska Territory, including Nebraska, North Dakota, South Dakota, part of Montana, and part of Wyoming.
One region he surveyed was the Minnesota River Valley, a valley much larger than what would be expected from the low-flow Minnesota River. In some places the valley is 5 miles (8 km) wide and 250 feet (80 m) deep. Warren first explained the hydrology of the region in 1868, attributing the gorge to a massive river, which drained Lake Agassiz between 11,700 and 9,400 years ago. The great river was named glacial River Warren in his honor after his death.
In the 1862 Peninsula Campaign, Warren commanded his regiment at the Siege of Yorktown and also assisted the chief topographical engineer of the Army of the Potomac, Brig. Gen. Andrew A. Humphreys, by leading reconnaissance missions and drawing detailed maps of appropriate routes for the army in its advance up the Virginia Peninsula. He commanded a brigade (3rd Brigade, 2nd Division, V Corps) during the Seven Days Battles and was wounded in the knee at the Battle of Gaines' Mill, although he refused to be taken from the field. At the Battle of Malvern Hill, his brigade stopped the attack of a Confederate division. He continued to lead the brigade at the Second Battle of Bull Run, suffering heavy casualties in a heroic stand against an overwhelming enemy assault, and at Antietam, where V Corps was in reserve and saw no combat.
Warren was promoted to brigadier general on September 26, 1862, and he and his brigade fought in the Battle of Fredericksburg in December. When Maj. Gen. Joseph Hooker reorganized the Army of the Potomac in February 1863, he named Warren his chief topographical engineer and then chief engineer. As chief engineer, Warren was commended for his service in the Battle of Chancellorsville.
At the start of the Gettysburg Campaign, as Confederate General Robert E. Lee began his invasion of Pennsylvania, Warren advised Hooker on the routes the Army should take in pursuit. On the second day of the Battle of Gettysburg, July 2, 1863, Warren initiated the defense of Little Round Top, recognizing the importance of the undefended position on the left flank of the Union Army, and directing, on his own initiative, the brigade of Colonel Strong Vincent to occupy it just minutes before it was attacked. Warren suffered a minor neck wound during the Confederate assault.
Promoted to major general after Gettysburg (August 8, 1863), Warren commanded II Corps from August 1863 until March 1864, replacing the wounded Maj. Gen. Winfield S. Hancock, and distinguishing himself at the Battle of Bristoe Station. (On March 13, 1865, he was breveted to major general in the regular army for his actions at Bristoe Station.) During the Mine Run Campaign, Warren's corps was ordered to attack Lee's Army, but he perceived that a trap had been laid and refused the order from Army commander Maj. Gen. George G. Meade. Although initially angry at Warren, Meade acknowledged that he had been right. Upon Hancock's return from medical leave, and the spring 1864 reorganization of the Army of the Potomac, Warren assumed command of V Corps. He led the V Corps through the Overland Campaign, the Siege of Petersburg, and the Appomattox Campaign.
During these Virginia campaigns, Warren established a reputation of bringing his engineering traits of deliberation and caution to the role of infantry corps commander. He won the Battle of Globe Tavern, August 18 to August 20, 1864, cutting the Weldon Railroad, a vital supply route north to Petersburg. He also won a limited success in the Battle of Peebles' Farm in September 1864, carrying a part of the Confederate lines protecting supplies moving to Petersburg on the Boydton Plank Road.
The aggressive Maj. Gen. Philip Sheridan, a key subordinate of Lt. Gen. Ulysses S. Grant, was dissatisfied with Warren's performance. He was angry at Warren's corps for supposedly obstructing roads after the Battle of the Wilderness and its cautious actions during the Siege of Petersburg. At the beginning of the Appomattox Campaign, Sheridan requested that the VI Corps be assigned to his pursuit of Lee's army, but Grant insisted that the V Corps was better positioned. He gave Sheridan written permission to relieve Warren if he felt it was justified "for the good of the service." Grant later wrote in his Personal Memoirs,
At the Battle of Five Forks on April 1, 1865, Sheridan became enraged with Warren's performance. He perceived that the V Corps moved too slowly into the attack and faulted Warren for not being at the front of his columns when Sheridan went to confront him. Warren in fact was handling dispositions of his divisions in a manner consistent with that a corps commander, and the attack by the V Corps carried the day at Five Forks, arguably the pivotal battle in the final days against Lee's army. Nevertheless, Sheridan relieved Warren of command on the spot. He was assigned to the defenses of Petersburg and then briefly to command the Department of Mississippi.
Warren died in Newport, Rhode Island, and was buried there at his request in civilian clothes and without military honors. His last words were, "The flag! The flag!
A bronze statue of Warren stands on Little Round Top in Gettysburg National Military Park, dedicated 20 years after the famous battle. Another bronze statue, by Henry Baerer (1837 – 1908), was erected in the Grand Army Plaza, Brooklyn, New York. It depicts Warren standing in uniform, with field binoculars on a granite pedestal, made of stone quarried at Little Round Top.