After two years at the University of North Carolina (1821–23), Polk entered the U.S. Military Academy at West Point, from which he was graduated in 1827. But during his final year there, Polk underwent a profound religious experience and resigned his commission at the end of 1827 to enter the Virginia Theological Seminary.

In 1830 Polk was ordained a deacon in the Protestant Episcopal Church, and in May 1831 he was advanced to the priesthood. He was appointed missionary bishop of the Southwest in 1838 and was made bishop of Louisiana in 1841. Polk attempted to combine his religious duties with life as a benevolent and paternalistic planter, since by marriage he acquired a large number of slaves. Polk also turned his energies toward creating an Episcopal university in the South, dedicated to training Southern aristocrats in their responsibilities toward blacks, who Polk anticipated would be gradually emancipated. In 1856 he began to raise funds and acquire land for the school, and on Oct. 9, 1860, he laid the cornerstone for the University of the South at Sewanee, Tenn.

With the coming of the Civil War, Polk, after some hesitation, accepted a commission as major general in the Confederate Army. Put in charge of defending the Mississippi River, Polk performed well despite his lack of practical military experience. On Nov. 7, 1861, he defeated Ulysses S. Grant's smaller force at Belmont, Mo., and he personally led four charges at Shiloh while in command of the Confederate right flank. In October 1862 he was promoted to lieutenant general. Polk sustained fatal wounds in fighting at Pine Mountain, Ga., in June 1864—four years before classes opened at the University of the South.