A resident of the state of Kentucky, Tilghman chose to enter the Confederate army in 1861. In February 1862 he was put in charge of Fort Donelson, which he subsequently defended against the attacks of General Ulysses S. Grant. He was taken prisoner and not exchanged until fall of 1862. He rejoined the service as a brigade commander in the Army of the West. He served at the Battle of Corinth in October 1862. However, in the following year, at the Battle of Champion's Hill, he is struck in the chest with a shell fragment, which killed him instantly.