He was elected governor in 1849 as a Democrat, and served from January 10, 1850, until his resignation on February 3, 1851, shortly after his arrest for violating U.S. neutrality laws.

Not counting house servants, at Palmyra, he enslaved 311 people under sixty years of age in 1848; at Live Oaks, 85 in 1850; at Springfield, 39 in 1842; and at Belen, 32 in 1858.

[9][10] The Natchez Fencibles were not selected to fight in the Mexican War due to a handful of men who failed to muster at Vicksburg at the proper time.

He led the 2nd Brigade in the Volunteer Division during the Siege of Veracruz, and on April 14, 1847, he was promoted to major general in the Regular Army.

Following the battle of Cerro Gordo, General Robert Patterson returned to the United States with other Volunteer soldiers whose enlistments had expired.

By this point, Quitman had gained a reputation as a competent military commander and enjoyed affectionate respect from volunteer and professional soldiers alike.

[12] Quitman led his division to the Valley of Mexico, where he was posted to guard the supply depot, hospital, and horse teams.

It was in his capacity as governor of Mississippi that Quitman was approached by the Venezuelan filibuster Narciso López to lead his expedition of 1850 to liberate Cuba from Spanish rule.

López's effort failed, and the repercussion led to Quitman's being charged with violations of Neutrality Act of 1817 and his resignation from the post of the governor so that he could defend himself.

With the encouragement of President Franklin Pierce, Quitman, with assistance from later Confederate General Mansfield Lovell,[13] began preparations in July 1853 for a filibuster expedition of his own.

John A. Quitman died at his home, "Monmouth," near Natchez, Mississippi, on July 17, 1858, aged 59, apparently from the effects of National Hotel disease, which he contracted during the inauguration of President James Buchanan.

A Confederate steamboat which was provided by the State of Louisiana for the defense of New Orleans and armed with two rifled 32 pounders was named in his honor.