He then returned to teach at West Point, where he rose to become the Superintendent of the Military Academy, then resigned when Louisiana seceded from the Union. Beauregard was one of 8 full generals in the Confederate Army. He recommended stationing strong forces to protect New Orleans, but was overruled by Jefferson Davis; this started friction between Beauregard and Davis that would only get worse as years progressed. Beauregard's first assignment from the Confederate Government was command of the forces in Charleston, South Carolina, where on April 12, 1861 he opened fire on the Union held Fort Sumter, regarded as the start of the American Civil War.

He led Confederate forces to victory in the First battle of Manassas, and commanded with mixed results until forced to withdraw at the Battle of Shiloh. Beauregard successfully defended Charleston from repeated Union attacks 1862 - 1864. In 1864 he was appointed commander of Confederate forces in the West, where he fought without success to halt the advances of superior Union forces under U. S. Grant and William T. Sherman. He surrendered to the Union in April 1865.

After the war he spoke in favor of civil and voting rights for the recently freed slaves, an opinion not common among high-ranking Confederates.

Beauregard's military writings include The Principles and Maxims of the Art of War, Report on the Defense of Charleston, and A Commentary on the Campaign and Battle of Manassas. Beauregard and Jefferson Davis published a series of bitter accusations and counter-accusations, blaming each other in retrospect for the defeat of the Confederacy.

General Beauregard declined offers to take command of the armies of Romania (1866) and Egypt (1869).

He became involved in promotion of railroads, both as a company director and a consulting engineer. He invented a system of cable-powered street railway cars.

He served in the government of the State of Louisiana, first as adjutant general, and then less successfully as manager of the Louisiana State Lottery. Though considered personally honest, he failed to reform corruption in the Lottery system.

P.G.T. Beauregard died in New Orleans. He was buried in Metairie Cemetery.