With his state's secession from the Union, Isaac returned to Burke County, and with his brother Alphonso, recruited Company E of the 6th North Carolina Regiment. As captain, Avery commanded the company, which fought in the First Battle of Bull Run and the Battle of Seven Pines. In the summer of 1862, he was promoted to colonel. He was wounded at Gaines' Mill and was out of action until late in the fall. Avery's recovery caused him to miss the battles at Second Bull Run and Antietam. Following the reorganization of the army after the Battle of Fredericksburg, the 6th North Carolina was placed under the command of veteran Brig. Gen. Robert F. Hoke.