At the battle of Bull Run, Hampton commanded some 600 infantry that were positioned on Henry House Hill. As the Union pushed back the faltering brigades of Bartow, Bee, and Evans from Matthews’ Hill, Stonewall Jackson’s brigade arrived, accompanied by Hampton’s 600-man Legion. Hampton’s soldiers bought Jackson time to deploy as they delayed the attacking blue columns. Sherman’s brigade of blue-clad soldiers were mauled by Hampton’s volleys as they advanced. The 79th New York was thoroughly decimated by Hampton's musket fire and began to disintegrate.

As Stonewall Jackson ordered his counterattack, Hampton accompanied the Virginians and shattered the Union line. Of the 600, the Legion lost 121 men. Hampton was wounded by a Yankee bullet that creased his forehead but he continued to lead his men forward. By the end of the year, each element of the Legion had been expanded with new companies to bolster their effective combat strength.

In June, 1862, Robert E. Lee reorganized the Army of Northern Virginia. This reorganization split the three components of the original Legion into separate entities. The infantry element, under the command of Lt. Colonel Gary, was assigned to John Bell Hood's elite "Texas Brigade." At the Battle of 2nd Manassas, Hampton’s Legion led the charge of Hood’s brigade that shattered the massive 10thNY and 5thNY regiments, securing Chinn Ridge for the Southerners.

At the battle of Antietam, Hampton’s Legion would take part in Hood’s counterattack through the cornfield. After halting the Union advance, the brigade plunged into the cornfield, driving back the Yankees in a confused panic. Hood’s counterattack might very well have been the saving grace for Jackson’s flank as it allowed time for Lafayette McLaws’ and Walker’s divisions to arrive and stabilize the situation. The Legion suffered 50 casualties in the cornfield.

After suffering horrendous losses throughout 62’, the Legion was sent to Richmond to regain its strength and replenish its ranks. The infantry of the Legion missed the battle of Gettysburg but were sent South with Longstreet and fought at the battle of Chickamauga in September. The Legion was sent back to Virginia for the Overland Campaign in March, 1864, and fought in Micah Jenkins’ brigade at the Wilderness. During the Siege of Petersburg, the regiment was redesignated as Mounted-infantry and served under Fitzhugh Lee from June until the end of the war. Hampton’s Legion surrendered at Appomattox with 238 men and officers.

The cavalry battalion of Hampton’s Legion was consolidated with the 4th South Carolina Cavalry Battalion and two independent companies in August, and became the 2nd South Carolina Cavalry under Colonel Matthew Calbraith Butler. The 2ndSC Cavalry would serve in Hampton’s Brigade of Cavalry and then Hampton’s Division until the end of the war. The 2nd SC Cavalry were still known colloquially as “Hampton’s Legion” and became some of the most famous and feared horsemen in the civil war. Hampton’s Cavalry brigade became known as arguably Lee’s best horsemen. Hampton’s Brigade consisted of the 1st NC Cavalry, the 2nd South Carolina Cavalry, Cobb’s Georgia Legion Cavalry, Philip’s Georgia Cavalry Legion, and the Jeff Davis Legion.

At the battle of Antietam in September, 1862, Hampton led his troops on the left flank of the Confederate line around Nicodemus hill. His brigade was selected to participate in Stuart's Chambersburg Raid in October 1862, in which Hampton was briefly appointed "military governor" of the town following its surrender to the Confederate cavalry.

During the winter of 1862, Hampton led a series of cavalry raids behind enemy lines and captured numerous prisoners and supplies without casualties, earning a commendation from General Lee. In November 1862, he captured 137 men of the 3rd Pennsylvania Cavalry at Hartwood Presbyterian Church.

At the battle of Brandy Station on June 9th, 1863, Hampton’s brigade fought tooth and nail against the Federal surprise attack. The battle was a confused swirling melee and Hampton was in the thick of the fighting as usual.

Hampton accompanied Stuart northwards into Pennsylvania and arrived at Gettysburg on the second day. On July 3rd, as Pickett began his charge, a massive cavalry battle ensued to the East of the Confederate line. While just outside town, after arriving on the 2nd, Hampton was confronted by a U.S. cavalryman pointing a rifle at him from 200 yards. Hampton charged the soldier before he could fire his rifle, but another soldier blindsided Hampton with a saber cut to the back of his head. On July 3, Hampton led the cavalry attack east of Gettysburg, attempting to disrupt the U.S. rear, but collided with U.S. cavalry. He received two more saber cuts to the front of his head but continued fighting until he was again wounded with shrapnel to the hip. Hampton was carried back to Virginia in the same ambulance as John Bell Hood. On August 3, 1863, Hampton was promoted to major general and received command of a cavalry division.

For the rest of the war, Hampton lost no cavalry battles. During the Overland Campaign of 1864, Hampton's cavalry fought at the Battle of Todd's Tavern during the Battle of the Wilderness. It patrolled the left flank of the Confederate position at the Battle of Spotsylvania Court House, during which time J.E.B. Stuart was killed at the Battle of Yellow Tavern. Hampton escorted Lee's withdrawal to Richmond, fighting at the Battle of North Anna and the Battle of Haw's Shop before being detached from Lee's army to deal with Maj. Gen. Philip Sheridan's cavalry destroying central Virginia's railroad.

He distinguished himself further with a victory at the Battle of Trevilian Station. After his return to Richmond, he fought at the Battle of Nance's Shop and was given command of the Cavalry Corps on August 11, 1864.

In September, Hampton conducted what became known as the "Great Beefsteak Raid", where his troopers captured over 2400 heads of cattle and more than 300 prisoners behind enemy lines. While Lee's army was bottled up in the Siege of Petersburg, in January 1865, Hampton returned to South Carolina to recruit soldiers. He was promoted to Lieutenant General on February 14, 1865, but eventually surrendered to the United States along with General Joseph E. Johnston's Army of Tennessee at Bennett Place in Durham, North Carolina. Hampton was reluctant to surrender and nearly got into a personal fight with U.S. Brig. Gen. Judson Kilpatrick (often called "Kill-Cavalry") at the Bennett Farm.

By the end of the war, Wade Hampton III had garnered a reputation unlike any other Cavalryman in the East. Arguably even surpassing that of JEB Stuart. His tactical and strategic acumen was legendary and historians agree that Hampton is on the same pedestal as Nathan Bedford Forrest and JEB Stuart in terms of the greatest cavalry commanders of the civil war.