Col. Robert R. Garland mustered the Sixth Texas Infantry at Camp Henry E. McCulloch near Victoria, Texas, on November 14, 1861, and was confirmed as colonel on December 12, 1861. Garland asked the ladies of Victoria to make a flag for his regiment. Elizabeth McAnulty Owens, wife of Richard Owens, and her daughters sewed the original flag from fabric from her husband's mercantile store. The staff officers included Thomas Scott Anderson as lieutenant colonel, Alexander M. Haskell as major, Rhoads Fischer as major, Alexander H. Phillips, Jr., as major, Capt. Udalpha Wolf as quartermaster, Capt. J. K. P. Campbell as commissary, Samuel J. Garland as adjutant, and J. H. Bendine as sergeant major. The regiment was initially composed of ten companies of men from the counties of Calhoun, Lavaca, Victoria, Gonzales, Matagorda, Guadalupe, Hays, Bell, Travis, Dewitt, Coryell, and Bexar. The Sixth Texas Infantry served on both sides of the Mississippi River during its career. The regiment began on the western side until captured at the battle of Arkansas Post on January 11, 1863, and served in the Army of Tennessee on the eastern side for the remainder of the war.
The Sixth Texas Infantry was involved in numerous small engagements and skirmishes throughout the war. At one time the regiment remained under fire for sixty consecutive days. On October 28, 1861, the unit was assigned to assist the Texas Volunteer forces at Matagorda. The troops were excellently armed and were issued "butternut" colored uniforms manufactured at the Texas State Penitentiary at Huntsville. They were then assigned to Garland's Brigade in the District of Arkansas. The regiment remained in camp at Victoria until May 22, 1862, when they proceeded to Arkansas. They were captured at Fort Hindman during the battle of Arkansas Post. The regiment had 53 men disabled of the 542 engaged, and Colonel Garland reported 8 killed, 24 wounded, and 21 missing after the battle. The men were relocated to federal prison camps across Illinois, including Camp Butler, Camp Chase, and Camp Douglas, where they remained for three months until paroled in April 1863. The men were transported by train to Williamsport, Pennsylvania, on the way to be exchanged at City Point, Virginia. The flag of the Sixth Texas Infantry was taken at Williamsport where it remained in possession of the Lycoming County Historical Society and Museum in Williamsport until 1991, when the museum decided to return the flag to Texas and chose the Texas Heritage Museum at Hill College in Hillsboro Texas as the recipient.
In May 1863 the regiment assisted in preventing the capture of Richmond by Union Gen. George Stoneman. In July 1863 the Sixth Texas Infantry was reorganized. It was transferred to the Army of Tennessee in September and placed in Gen. Patrick R. Cleburne's Division. On September 19–20, at the battle of Chickamauga, the regiment reported 20 killed, 95 wounded, and 28 missing of the 667 engaged. The brigade endured some of the bloody battle's worst fighting while defending a hill on the Confederate right. From September 23 through November 24, 1863, the regiment participated in the siege of Chattanooga. In November 1863 the regiment was consolidated into what became known as "Granbury's Texas Brigade." On November 24–25, they assaulted and captured Missionary Ridge. They held the northern end of the ridge where they protected the Confederate flank from 20,000 advancing Union forces. Later in November the regiment participated in an engagement at Ringgold Gap. In December 1863 the regiment totaled 642 men and 437 arms. They were again consolidated in early 1864 with the Sixth, Tenth, and Fifteenth Dismounted Texas Cavalry and placed under the command of Col. Roger Quarles Mills. In February 1864 the regiment saw action at Tunnell Hill, Dug Gap, Buzzard's Roost Gap, Snake Creek Gap, and Rocky Ridge in Georgia.
The Sixth Texas Infantry was yet again consolidated in 1864 with the Fifteenth Dismounted Texas Cavalry under the command of Capt. Rhoades Fisher, until he was replaced by returning Col. Robert R. Garland on May 1, 1864. Upon his return the unit fought in the Atlanta campaign from May 1 through September 8, 1864. During the month of May the regiment participated in engagements at Rocky Faced Ridge, Resaca, Cassville, Pumpkin Vine Creek, and Dallas. Garland remained in command until after the battle of New Hope Church, Georgia, on May 25, 1864. Captain Fisher took command of the regiment until he was wounded in the Atlanta campaign. In June 1864 the regiment was involved in operations at Marietta, Kennesaw Mountain, Nickajack Creek, along the Chattahoochie River, Peach Tree Creek, and at Bald Hill. Captain Fischer again assumed command after the battle of Jonesboro until he was captured on the enemy's works at Franklin, Tennessee. Granbury's Brigade joined Gen. John Bell Hood's ill-fated campaign into Tennessee. The regiment was decimated at the battle of Franklin in November 1864, where Granbury, Cleburne, and five others were killed. General Cleburne was wounded in the chest, while Granbury was fatally wounded in the eye and instantly fell dead. During the final year of the war the regiment participated in engagements at Atlanta, Lovejoy Station, Jonesboro, Dalton, Spring Hill, Franklin, Nashville, and Bentonville. The regiment endured yet another consolidation on April 9, 1865, at Smithfield, North Carolina.
The Sixth Texas Infantry finally surrendered with Gen. Joseph E. Johnston's army at Durham Station, North Carolina, on April 26, 1865. At the time of surrender the regiment had less than fifty men fit for duty and was under the command of a lieutenant as all officers of higher rank were killed, wounded, or captured.