After South Carolina seceded from the Union, Ripley became a lieutenant colonel in the Army of South Carolina. He and his men garrisoned in Fort Moultrie. He directed the fort during the bombardment of Fort Sumter in Charleston Harbor on April 13, 1861. On August 15, 1861, he was appointed as a brigadier general in the Confederate Army and assigned command of the Department of South Carolina and its coastal defenses. From December 1861 until May 1862, he had charge of the Second Military District of South South Carolina.[3] In the Spring of 1862, slave Robert Smalls along with a slave crew, stole from Charleston Harbor a high-pressure side-wheeler steam powered ship, the 147-foot long “Planter”. Brigadier General Roswell S Ripley was astonished when his troops told him that the “Planter” had vanished from her berth directly in front of Ripley’s headquarters on the Charleston wharf.
Transferred to field command in Virginia, Ripley commanded an infantry brigade (comprising two Georgia and two North Carolina regiments) in the defenses of Richmond, Virginia, in June 1862. Assigned to the Army of Northern Virginia, Ripley's Brigade participated in the battles of Mechanicsville, Gaines Mill, and Malvern Hill during the Peninsula Campaign.[4]
Despite being depleted from recent fighting and illness, Ripley's Brigade fought in the Maryland Campaign at the Battle of South Mountain and the Battle of Sharpsburg in September 1862. He suffered a severe wound in the neck at Sharpsburg, but soon recovered and rejoined the army. In November, he was involved in the defense of Fredericksburg.
Criticized for his performance at Antietam, General Ripley in early 1863 returned to South Carolina and took charge of the First Military District. His men constructed a series of improved defenses around Charleston, and Ripley commanded the troops that repelled a Union Navy attack on April 7, 1863. He continued in command of Charleston's fortifications until the city was evacuated in mid-February 1865 and fought under Joseph E. Johnston at the Battle of Bentonville.