In November 1862, Grierson became a brigade commander in the cavalry division of the Army of the Tennessee. He was promoted to brigadier general of volunteers in June 1863, shortly before leading his brigade on a highly-successful raid deep into enemy territory that drew Confederate resources away from Ulysses S. Grant's Vicksburg assault. In 1864 Grierson was appointed commander of a cavalry division in the Army of the Tennessee, then commander all cavalry units in the District of West Tennessee, and finally commander of the Cavalry Corps of the Army of the Mississippi.
When the war ended, Grierson chose to remain in the Regular Army and was appointed a colonel in the cavalry. In 1866, he organized the 10th U.S. Cavalry, a unit composed entirely of African American troopers, which came to be known as the Buffalo Soldiers. Grierson's faith in these troops, his respect for Native American culture and his lack of West Point credentials all combined to distance him from his fellow officers and superiors. Nevertheless, Grierson went on to a distinguished career in the post-war army and he retired a brigadier general in 1890.