[citation needed] Twiggs was commissioned as Colonel of the 2nd U.S. Dragoons in 1836 and served in the Seminole Wars in Florida, where he earned the nickname "Bengal Tiger" for his fierce temper.

[citation needed] During the Mexican–American War (1846–1848), Twiggs led a brigade in the Army of Occupation at the battles of Palo Alto and Resaca de la Palma.

He was an original member of the Aztec Club of 1847, a military society of officers who had served in the Mexican War.

[8] After the Mexican–American War, Twiggs was appointed brevet major general and commanded the U.S. Army's Department of Texas.

[2] He was one of five general officers in the U.S. Army in 1861, along with Winfield Scott, John Wool, Joseph E. Johnston, and William Harney.

As there was then no mandatory retirement, all but Johnston were over the age of 60, with three (Scott, Twiggs, and Wool) having served in the War of 1812 half a century earlier.

As states began to declare secession, he met with a trio of Confederate commissioners, including Philip N. Luckett and Samuel A. Maverick.

[2] He insisted that all U.S. soldiers be allowed to retain personal arms and sidearms, all artillery[dubious – discuss], and flags and standards.

He was assigned to command the Confederate Department of Louisiana (comprising that state along with the southern half of Mississippi and Alabama), but he was past the age of 70 and in poor health.