In 1861, Granger's unit on the frontier became the 3rd U.S. Cavalry. He first served at the Battle of Wilson's Creek, Missouri, which earned him a promotion to the colonel of the 2nd Michigan Cavalry. In the Battle of New Madrid and Island No. 10, he commanded a brigade. He received a promotion to brigadier general in March 1862, then to major general in September 1862. In September 1863, he distinguished himself by marching to the rescue in the Battle of Chickamauga. In the subsequent Battle of Chattanooga, he commanded the IV corps. He was involved in the relief of Knoxville, and the actions against Fort Gaines and Fort Morgan, which resulted in the eventual capture of Mobile in 1865. He continued to serve in the regular army after the end of the war.