When the American Revolution broke out, Jackson and his brothers leapt at the chance to fight the British. Jackson's mother had regaled her sons with stories of the battle for freedom in their native Ireland, including tales of how Jackson's grandfather had fought against the British in Ireland and participated in the siege of Carrickfergus. For Jackson's family, fighting the British was more of a personal affair than a political one.

Jackson was only nine years old when the Founders signed the Declaration of Independence in Philadelphia. It was several years, however, before the war of independence would reach the Southern colonies. In 1780, the British launched an invasion of South Carolina and captured Charleston on May 12. Groups of soldiers and Tory sympathizers began to loot and pillage the countryside. Three hundred soldiers under the command of Lt. Col. Banastre Tarleton leveled much of the Waxhaws settlement, surprising a force of several hundred American patriots and killing more than hundred of them. The massacre sparked widespread outrage, as many bodies were mutilated and some had suffered more than a dozen wounds. The approximately 150 wounded were put up in the Waxhaw church, where residents, including the Jackson family, tended to the wounds and administered first aid. After the Waxhaw massacre, Jackson's older brother Hugh joined the patriot regiment commanded by Colonel William R. Davie. Soon thereafter, Hugh died from heat exhaustion at the Battle of Stono Ferry.

As the war in the South widened, Jackson began to travel with American troops and participated in the assault on the small British post of Hanging Rock–an attack that the patriots could have won decisively if they had not stopped to drink captured rum from the post. As Jackson was only thirteen, he worked on the staff of Colonel Davie, the patriots' commander, mostly running errands or delivering messages. Jackson's position as Davie's assistant was his first exposure to military command, and many of his later military strategies would reflect the bold planning and careful execution that typified Davie.

In the late summer of 1780, General Charles Cornwallis, the British southern commander, gained a strong upper hand following the battle of Camden, which left the patriots in tatters. As Cornwallis marched towards the Waxhaws, a yearlong battle of attrition began. After a small engagement near Waxhaw, Jackson and his remaining brother, Robert, hid in the house of their relative, Thomas Crawford. British dragoons discovered the two–thus beginning a nearly fatal chapter of Jackson's life. Upon discovering the two Jackson boys, the British detachment began to destroy the house, tearing apart furniture and breaking windows. The prisoners cowered in the living room until the British commander ordered Andrew to clean the mud from the soldiers' boots. Jackson refused, replying, "Sir, I am a prisoner of war and claim to be treated as such." In an angry response, the soldier raised his sword and swung at the boy's head. Jackson managed to deflect part of the blow with his left hand, but he received a serious gash on his hand and another on his head–two scars of British ire that Jackson would bear for the rest of his life. When Robert also refused to clean the boots, he was sent staggering across the room by a blow from the officer's sword.

The British took the two Jackson boys and twenty other prisoners from the battle to Camden, nearly forty miles away. There, the British placed all of them into a small prisoner camp with 250 other men, with no medicine, no beds, and only a small amount of bread for food. Both boys became infected with smallpox and would have likely died had their mother, Elizabeth, not helped to arrange a prisoner transfer–the patriots turned over thirteen redcoats and the British freed seven prisoners, including the two Jacksons. Andrew walked the forty miles back to Waxhaw, while his mother and his dying brother rode beside him. Robert died two days after returning home, and it was several weeks before Andrew regained enough of his health to leave his bed.

After Andrew regained his strength, his mother left to tend to other soldiers in Charleston. She and other Waxhaw helped soldiers held prisoner in prison ships in the harbor. The work was hard, and she took ill with "ship's fever"–cholera–and passed away at the house another relative in Charleston. As a notice of Elizabeth's death, relatives sent Andrew a small pile of her belongings. In short order, then, the war had claimed every remaining member of Andrew's family.

Andrew returned to live in the house of his uncle, Thomas Crawford–the house where he and Robert had been captured. This living situation did not work out very well, as the war had made Jackson quite bitter and angry. The issue came to a head when a soldier living with Crawford, Captain Galbraith, responded angrily to something Jackson said and raised his hand as if to slap the young man–exactly the movement that the British officer had made with his sword earlier. Jackson exploded, jumping up and yelling that if the Captain touched him the soldier would die. Jackson soon thereafter moved in with another relative, from whom he also learned the trade of saddle making.

In 1781, the same year as Jackson's mother died, General Cornwallis surrendered the British forces at Yorktown, effectively ending the Revolution. As peace began and the well-to-do families of Charleston waited for the British withdrawal in Waxhaw, Jackson began to take up a rather colorful lifestyle. He began participating in card games, cockfighting, and horse racing. When he received a four-hundred-pound inheritance from his grandfather, Jackson blew it all in one quick spending spree. Broke and on his way out of town, he happened upon a dice game called "Rattle and Snap." A player bet two hundred dollars and Jackson put up his horse. Jackson won, paid off his other gambling debts and left Charleston for good.