With Alabama's secession from the Union, Fry enlisted in the Confederate army and was appointed Colonel of the 13th Alabama Infantry. The regiment was transported to Virginia and fought in the Peninsula Campaign. Colonel Fry was wounded in action at the Battle of Seven Pines. He recovered in time to command his regiment in the savage fighting at Antietam, where he was again wounded, suffering a shattered arm. Fry rejoined his regiment and led it during the 1863 Battle of Chancellorsville, where he suffered a third wound. During the subsequent Gettysburg Campaign, Fry's regiment was among the first Confederate units to deploy into battleline and engage the Union cavalry of John Bufordat the opening of the Battle of Gettysburg on July 1, 1863. His men suffered considerable casualties as the day progressed after being driven off McPherson's Ridge by the arrival of the Federal Iron Brigade. With the capture of Brig. Gen. James J. Archer, Fry assumed command of Archer's Brigade of Tennesseans and Alabamians. Held in reserve on July 2, Fry's brigade was a key part of the July 3 attack that became famous as Pickett's Charge. He suffered yet another wound, and fell near the Union lines. Fry was treated in a local field hospital then held as a prisoner of war at Fort McHenry in Baltimore, There, rumors circulated that Fry had been involved in the August 1862 murder of Union general Robert L. McCook in Alabama. Fry's West Point classmate, John Gibbon, who ironically commanded the troops that had shot Fry at Gettysburg, vouched for his character and the matter was forgotten. Exchanged in 1864, Fry rejoined the Army of Northern Virginia in time for the beginning of the Siege of Petersburg. During Philip H. Sheridan's raid on Richmond in early May, Fry was assigned command of Seth Barton's Virginia brigade, leading it during the Battle of Meadow Bridge. He was promoted to brigadier general on May 24, 1864. During the final months of the war, Fry was placed in command of a military district in South Carolina and Georgia.
Postbellum
After surrendering in Augusta, Fry emigrated to Cuba at the close of hostilities, lodging in Havana hotels with several other former prominent Confederates, including Jubal A. Early, John C. Breckinridge, Robert A. Toombs, and John B. Magruder, among others. He did not return to the United States until 1868, when he returned to Tallassee, Alabama as a businessman. He resided at No. 1, King Street, in a house built for Confederate Officers in charge of the Tallassee Armory. His home is still standing and after renovations now serves as the law offices of The Segrest Law Firm. Fry later expanded his business career in Florida, and, in 1881, moved to Richmond, Virginia, where he was president of a cotton mill for a decade. Fry died in Richmond on January 21, 1891 and was buried in Oakwood Cemetery in Montgomery, Alabama.