On April 11, Beauregard sent three aides, Colonel James Chesnut, Jr., Captain Stephen D. Lee, and Lieutenant A. R. Chisolm to demand the surrender of the fort. Anderson declined, and the aides returned to report to Beauregard. After Beauregard had consulted the Secretary of War, Leroy Walker, he sent the aides back to the fort and authorized Chesnut to decide whether the fort should be taken by force. The aides waited for hours while Anderson considered his alternatives and played for time. At about three a.m., when Anderson finally announced his conditions, Colonel Chesnut, after conferring with the other aides, decided that they were "manifestly futile [..] and not within the scope of the instructions verbally given to us". The aides then left the fort and proceeded to the nearby Fort Johnson. There Chesnut ordered the fort to open fire on Fort Sumter.

On April 12, 1861, at 4:30 a.m., Confederate batteries opened fire, firing for 34 straight hours, on the fort. Edmund Ruffin, noted Virginian agronomist and secessionist, claimed that he fired the first shot on Fort Sumter. His story has been widely believed, but Lieutenant Henry S. Farley, commanding a battery of two mortars on James Island fired the first shot at 4:30 A.M. The garrison returned fire, but it was ineffective, in part because Major Anderson did not use the guns mounted on the highest tier, the barbette tier, where the gun detachments would be more exposed to Confederate fire. On April 13, the fort was surrendered and evacuated. During the attack, the Union colors fell. Lt. Norman J. Hall risked life and limb to put them back up, burning off his eyebrows permanently. No Union soldiers died in the actual battle though a Confederate soldier bled to death having been wounded by a misfiring cannon. One Union soldier died and another was mortally wounded during the 47th shot of a 100 shot salute, allowed by the Confederacy. Afterwards the salute was shortened to 50 shots. Accounts, such as in the famous diary of Mary Chesnut, describe Charleston residents along what is now known as The Battery, sitting on balconies and drinking salutes to the start of the hostilities.

A special military decoration, known as the Gillmore Medal, was later issued to all Union service members who had performed duty in Fort Sumter during the opening battle of the American Civil War.

The Fort Sumter Flag became a popular patriotic symbol after Maj. Anderson returned North with it. The flag is still displayed in the fort's museum.

On April 12th, Maj. Robert Anderson and 127 men held Fort Sumter in Charleston Harbor, with Capt. Abner Doubleday being second in command. The men had been neither supplied nor reinforced since occupying the fort the night of December 26, 1860. Their presence caused a crisis between the U.S. government and the seceded state of South Carolina, offended at Union troops sitting on sovereign territory. Confederate forces, commanded by Brig. Gen. P.G.T. Beauregard, had thrown up batteries on the harbor's shores north and south of Fort Sumter and trained guns on it from Forts Moultrie and Johnson. Fort Sumter mustered only 66 cannon, several unmounted. At 3:20 A.M., the crisis came to a head.

The Confederate cabinet telegraphed Beauregard on April 10 to fire on Fort Sumter if absolutely necessary to prevent reinforcement. Capt. Stephen D. Lee and Col. James Chestnut, secessionists, rowed out to Fort Sumter and made a last demand for surrender. Anderson refused, but said he would be starved out in a few days anyway.

In 1860, South Carolina became the first state to secede from the United States. As more states followed suit and the Confederate States of America took shape, many federal installations in the South were taken over by state governments. Fort Sumter, in the harbor of Charleston, South Carolina, continued to fly the U.S. flag, even as Confederate forces surrounded it. Lincoln decided to resupply the fort but not reinforce it, unless resistance was met. After negotiations failed, the first shot was fired on April 12, 1861, in a bombardment that resulted in the fort's surrender. With that shot the Civil War began.