Thomas served in the Mexican-American War and later chose to remain with the United States Army for the Civil War, despite his heritage as a Virginian.

He won one of the first Union victories in the war, at Mill Springs in Kentucky, and served in important subordinate commands at Perryville and Stones River. His stout defense at the Battle of Chickamauga in 1863 saved the Union Army from being completely routed, earning him his most famous nickname, the "Rock of Chickamauga." He followed soon after with a dramatic breakthrough on Missionary Ridge in the Battle of Chattanooga. In the Franklin-Nashville Campaign of 1864, he achieved one of the most decisive victories of the war, destroying the army of Confederate General John Bell Hood, at the Battle of Nashville.

Thomas had a successful record in the Civil War, but he failed to achieve the historical acclaim of some of his contemporaries, such as Ulysses S. Grant and William T. Sherman. He developed a reputation as a slow, deliberate general who shunned self-promotion and who turned down advancements in position when he did not think they were justified. After the war, he did not write memoirs to advance his legacy. He also had an uncomfortable personal relationship with Grant, which served him poorly as Grant advanced in rank and eventually to the presidency.

Thomas was born at Newsom's Depot, five miles (8 km) from North Carolina, in Southampton County, Virginia. His father, John Thomas, of Welsh descent, and his mother, Elizabeth Rochelle Thomas, a descendant of French Huguenot immigrants, had nine children. George was a middle child and the youngest of the three boys. The family led an upper-class plantation lifestyle. By 1829, they owned 685 acres (2.77 km2) and 24 slaves.

John died in a farm accident when George was 13, leaving the family in financial difficulties. George Thomas, his sisters, and his widowed mother were forced to flee from their home and hide in the nearby woods during Nat Turner's 1831 slave rebellion. Benson Bobrick has suggested that while some repressive acts were enforced following the crushing of the revolt, Thomas took the lesson another way, seeing that slavery was so vile an institution that it had forced the slaves to act in violence. This was a major event in the formation of his views on slavery; that the idea of the contented slave in the care of a benevolent overlord was a sentimental myth.

Christopher Einholf, in contrast wrote "For George Thomas, the view that slavery was needed as a way of controlling blacks was supported by his personal experience of Nat Turner's Rebellion. ... Thomas left no written record of his opinion on slavery, but the fact that he owned slaves during much of his life indicates that he was not opposed to it." A traditional story is that Thomas taught as many as 15 of his family's slaves to read, violating a Virginia law that prohibited this, and despite the wishes of his father.

Thomas was appointed to the United States Military Academy at West Point, New York, in 1836 by Congressman John Y. Mason, who warned Thomas that no nominee from his district had ever graduated successfully. Entering at age 20, Thomas was known to his fellow cadets as "Old Tom" and he became instant friends with his roommates, William T. Sherman and Stewart Van Vliet. He made steady academic progress, was appointed a cadet officer in his second year, and graduated 12th in a class of 42 in 1840. He was appointed a second lieutenant in Company D, 3rd U.S. Artillery.

Thomas's first assignment with his artillery regiment began in late 1840 at the primitive outpost of Fort Lauderdale, Florida, in the Seminole Wars, where his troops performed infantry duty. He led them in successful patrols and was appointed a brevet first lieutenant on November 6, 1841. From 1842 until 1845, he served in posts at New Orleans, Fort Moultrie in Charleston Harbor, and Fort McHenry in Baltimore. With the Mexican-American War looming, his regiment was ordered to Texas in June 1845.

Thomas was reassigned to Florida in 1849–50. In 1851, he returned to West Point as a cavalry and artillery instructor, where he established a close professional and personal relationship with another Virginia officer, Lt. Col. Robert E. Lee, the Academy superintendent. Two of Thomas's students who received his recommendation for assignment to the cavalry, J.E.B. Stuart and Fitzhugh Lee, became prominent Confederate cavalry generals. Another Civil War connection was a cadet expelled for disciplinary reasons on Thomas's recommendation, John Schofield, who would excoriate Thomas in postbellum writings about his service as a corps commander under Thomas in the Franklin-Nashville Campaign.

On November 17, 1852, Thomas married Frances Lucretia Kellogg, age 31, from Troy, New York. The couple remained at West Point until 1854.

In the spring of 1854, Thomas's artillery regiment was transferred to California and he led two companies to San Francisco via the Isthmus of Panama, and then on a grueling overland march to Fort Yuma.

There was a suspicion as the Civil War drew closer that Davis had been assembling and training a combat unit of elite U.S. Army officers who harbored Southern sympathies, and Thomas's appointment to this regiment implied his colleagues assumed that he would support his native state of Virginia in a future conflict. Thomas resumed his close ties with the second-in-command of the regiment, Robert E. Lee, and the two officers traveled extensively together on detached service for court-martial duty.

In October 1857, Major Thomas assumed acting command of the cavalry regiment, an assignment he would retain for 2½ years. On August 26, 1860, during a clash with a Comanche warrior, Thomas was wounded by an arrow passing through the flesh near his chin area and sticking into his chest at Clear Fork, Brazos River, Texas. Thomas pulled the arrow out and, after a surgeon dressed the wound, continued to lead the expedition. This was the only combat wound that Thomas suffered throughout his long military career.

In November 1860, Thomas requested a one-year leave of absence. His antebellum career had been distinguished and productive, and he was one of the rare officers with field experience in all three combat arms—infantry, cavalry, and artillery. On his way home to southern Virginia, he suffered a mishap in Lynchburg, Virginia, falling from a train platform and severely injuring his back. This accident led him to contemplate leaving military service and caused him pain for the rest of his life. Continuing to New York to visit with his wife's family, Thomas stopped in Washington, D.C., and conferred with general-in-chief Winfield Scott, advising Scott that Maj. Gen. David E. Twiggs, the commander of the Department of Texas, harbored secessionist sympathies and could not be trusted in his post.

At the outbreak of the Civil War, 19 of the 36 officers in the 2nd U.S. Cavalry resigned, including three of Thomas's superiors—Albert Sidney Johnston, Robert E. Lee, and William J. Hardee. Many Southern-born officers were torn between loyalty to their states and loyalty to their country. Thomas struggled with the decision but opted to remain with the United States. His Northern-born wife probably helped influence his decision.

In response, his family turned his picture against the wall, destroyed his letters, and never spoke to him again. (During the economic hard times in the South after the war, Thomas sent some money to his sisters, who angrily refused to accept it, declaring they had no brother.)

Nevertheless, Thomas stayed in the Union Army with some degree of suspicion surrounding him. On January 18, 1861, a few months before Fort Sumter, he had applied for a job as the commandant of cadets at the Virginia Military Institute. Any real tendency to the secessionist cause, however, could be refuted when he turned down Virginia Governor John Letcher's offer to become chief of ordnance for the Virginia Provisional Army. On June 18, his former student and fellow Virginian, Confederate Col. J.E.B. Stuart, wrote to his wife, "Old George H. Thomas is in command of the cavalry of the enemy. I would like to hang, hang him as a traitor to his native state."

In the First Bull Run Campaign, he commanded a brigade under Maj. Gen. Robert Patterson in the Shenandoah Valley, but all of his subsequent assignments were in the Western Theater.

At the Battle of Chickamauga on September 19, 1863, now commanding the XIV Corps, he held a desperate position against Bragg's onslaught while the Union line on his right collapsed. Thomas rallied broken and scattered units together on Horseshoe Ridge to prevent a significant Union defeat from becoming a hopeless rout. Future president James Garfield, a field officer for the Army of the Cumberland, visited Thomas during the battle, carrying orders from Rosecrans to retreat; when Thomas said he would have to stay behind to ensure the Army's safety, Garfield told Rosecrans that Thomas was "standing like a rock." After the battle he became widely known by the nickname "The Rock of Chickamauga", representing his determination to hold a vital position against strong odds.

During the Reconstruction period, Thomas acted to protect freedmen from white abuses. He set up military commissions to enforce labor contracts since the local courts had either ceased to operate or were biased against blacks. Thomas also used troops to protect places threatened by violence from the Ku Klux Klan.

In 1869 he requested assignment to command the Military Division of the Pacific with headquarters at the Presidio of San Francisco. He died there of a stroke while writing an answer to an article criticizing his military career by his wartime rival John Schofield. None of his blood relatives attended his funeral as they had never forgiven him for his loyalty to the Union and not Virginia.

He was buried in Oakwood Cemetery, in Troy, New York.

Thomas has generally been held in high esteem by Civil War historians; Bruce Catton and Carl Sandburg wrote glowingly of him, and many consider Thomas one of the top three Union generals of the war, after Grant and William Tecumseh Sherman. But Thomas never entered the popular consciousness like those men.

The general destroyed his private papers, saying he did not want "his life hawked in print for the eyes of the curious." Beginning in the 1870s, many Civil War generals published memoirs, justifying their decisions or refighting old battles, but Thomas, who died in 1870, did not publish his own memoirs. In addition, most of his campaigns were in the Western theater of the war, which received less attention both in the press of the day and in contemporary historical accounts.