The fort was still unfinished when Major Robert Anderson moved his 85-man garrison into it on December 26, 1860, setting in motion events that would tear the nation asunder four months later.

On December 20, 1860, South Carolina delegates to a special secession convention voted unanimously to secede from the Federal Union. In November, Abraham Lincoln had been elected President of the United States with no support from southern states. The critical significance of this election was expressed in South Carolina's Declaration of the Immediate Causes of Secession: “A geographical line has been drawn across the Union, and all the States north of that line have united in the election of a man to the high office of President of the United States, whose opinions and purposes are hostile to slavery.” The Declaration claimed that secession was justified because the Federal Government had violated the Constitutional compact by encroaching upon the rights of the sovereign states. As the primary violation, the Declaration listed the failure of northern states to enforce the Federal Fugitive Slave Act or to restrict the actions of antislavery organizations. “Thus the constituted compact [the U.S. Constitution] has been deliberately broken and disregarded by the non-slaveholding States, and the consequence follows that South Carolina is released from her obligation.” The Declaration expressed South Carolina's fear that “The slaveholding States will no longer have the power of self-government, or self-protection, and the Federal Government will have become their enemy.”

As the country expanded, regional conflict centered on the extension of slavery into new American territories. Included in the arguments was the fate of enslaved African Americans fleeing from the South. Over decades, North and South tried and failed to reach agreements on geographic boundaries for slavery, the recapture of runaways, and the status of free blacks living throughout the nation. National political parties, religious denominations, and even families divided over these issues.

In the months between Lincoln's election and his inauguration, as more southern states proclaimed secession, efforts at compromise continued. Southern Unionists and their northern supporters believed that the Union could be restored without war if only the southern states had guarantees that the Federal Government would not interfere with their slave property. A Constitutional amendment guaranteeing the rights of slave owners was suggested, but Lincoln concluded that no plan of compromise would ever fully satisfy South Carolina, the state that led the South in defense of the rights of slaveholders and the right of secession.

Within six weeks after South Carolina's secession, five other states -- Mississippi, Florida, Alabama, Georgia, and Louisiana -- followed its example. Early in February, 1861, delegates met in Montgomery, Alabama, adopted a constitution, set up a provisional government -- the Confederate States of America -- and elected Jefferson Davis as their president. By March 2nd, when Texas officially joined the Confederacy, nearly all the Federal forts and navy yards in the seven seceding states had been seized by the new government. Fort Sumter was one of the few that remained in Federal hands.

When South Carolina seceded, there were four Federal installations around Charleston Harbor: Fort Moultrie on Sullivan's Island, Castle Pinckney on Shute’s Folly Island near the city, Fort Johnson on James Island across from Moultrie, and Fort Sumter at the harbor entrance.