Smith was wounded at the First Battle of Bull Run and distinguished himself during the Heartland Offensive, the Confederacy's unsuccessful attempt to capture Kentucky in 1862.

After the United States took control of Vicksburg in July, the Trans-Mississippi Department was cut off from the rest of the Confederacy and became virtually an independent nation, nicknamed "Kirby Smithdom".

On June 2, 1865, Smith surrendered his army at Galveston, Texas, the last general with a major field force.

His wife negotiated his return during the period when the U.S. government offered amnesty to those who would take an oath of loyalty to the United States.

In 1837, his sister Frances married Lucien Bonaparte Webster, a West Point graduate from Vermont and career U.S. Army artillery officer, whom she met when he was stationed at Fort Marion in St. Augustine.

Webster later served in the Mexican–American War and died of yellow fever in 1853 when stationed on the Texas frontier at Fort Brown.

[5] He later served under General Winfield Scott and received brevet promotions to first lieutenant for Cerro Gordo and to captain for Contreras and Churubusco.

His older brother, Ephraim Kirby Smith (1807–1847), who was graduated from West Point in 1826 and was a captain in the regular army, served with him in the 5th U.S. Infantry in the campaigns with both Taylor and Scott.

From that year on through the war, Smith was accompanied by the youth Alexander Darnes, then 15, a mixed-race person enslaved by his family, who was forced to work as his valet until emancipation and who may have been his half-brother.

[5] When Texas declared secession from the United States in 1861, Smith, promoted to major on January 31, 1861, refused to surrender his command at Camp Colorado in what is now Coleman, to the Texas State Troops under Colonel Benjamin McCulloch; he expressed his willingness to fight to hold it.

He remained west of the Mississippi River for the balance of the war, based part of this time in Shreveport, Louisiana.

However, his department never had more than 30,000 men stationed over an immense area, and he could not concentrate forces adequately to challenge Grant nor the U.S. Navy on the river.

[19] Following the U.S. capture of the remaining strongholds at Vicksburg and Port Hudson and their closing of the Mississippi to the Confederacy, Smith was virtually cut off from the Confederate capital at Richmond.

[22] After the Battle of Pleasant Hill on April 9, Smith joined Taylor and dispatched half of Taylor's army, Walker's Greyhounds, under the command of Major-General John George Walker, northward to defeat U.S. Major-General Frederick Steele's incursion into Arkansas.

But, as in the case of his earlier attempts to relieve Vicksburg, it proved impossible due to U.S. Navy control of the river.

Beauregard complained to General Sheridan, who expressed annoyance at the treatment of the high-ranking officer, his erstwhile enemy.

[26] Smith returned to the United States later that year to take an oath of amnesty at Lynchburg, Virginia, on November 14, 1865.

After the war's end, Cassie traveled to Washington to negotiate for her husband's return to the United States from Cuba, where he had fled.

They had five sons and six daughters: Caroline (1862–1941), Frances (1864–1930), Edmund (1866–1938), Lydia (1868–1962), Nina (1870–1965), Elizabeth (1872–1937), Reynold (1874–1962), William (1876–1967), Josephine (1878–1961), Joseph Lee (1882–1939), and Ephraim (1884–1938).

Joseph was a member of the famed 1899 "Iron Men" and Ephraim was selected for Sewanee's All-Time football team.