A veteran of the Mexican War, Prentiss joined the ranks of the 10th Illinois in 1861. In August 1861 he was promoted to brigadier general. The following year, as a division commander, he was blamed for the first day at Shiloh. Prentiss was exiled to eastern Arkansas, during which time he participated in the battles at Helena and at Vicksburg. In 1863, he cited health issues as a reason to resign his position.