He is most noted for Grierson's Raid, an 1863 expedition through Confederate-held territory that severed enemy communication lines between Vicksburg, Mississippi and Confederate commanders in the Eastern Theater.

In December, he participated in the pursuit of Confederate Earl Van Dorn after his Holly Springs raid against the supply lines of General Ulysses S. Grant.

In the spring of 1863, he led Grierson's Raid, a major diversionary thrust deep into the Confederacy, ordered by Grant as part of his Vicksburg Campaign.

Over 17 days, his command marched 800 miles, repeatedly engaged the Confederates, disabled two railroads, captured many prisoners and horses, and destroyed vast amounts of property, finally ending in Baton Rouge on May 2.

[2] Historian John D. Winters in The Civil War in Louisiana (1963) reports that Grierson's raid "struck fear in the hearts of the citizens and somewhat demoralized the Confederate forces who failed to stop the move.

On Christmas Day he surprised and captured Forrest's dismounted camp at Verona, Mississippi, and on December 28 engaged a train carrying an ad hoc Confederate force of approximately 1,200 men at Egypt Station, Mississippi, south of Aberdeen, capturing more than 500 troops, including 253 former Union prisoners who had enlisted as "Galvanized Yankees" in the 10th Tennessee.

On 28 July 1866 he was commissioned a colonel in the Regular Army and assigned as the commander of the 10th U.S. Cavalry, one of two mounted regiments composed of black enlisted men and white officers, called the Buffalo Soldiers.

Ostracized by other officers for his enthusiastic command of the African-American troops, Grierson believes in the abilities, dedication, and record of performance of the Buffalo Soldiers and declines offers to lead at any other post.

The part of Colonel Marlowe, played by John Wayne in the movie The Horse Soldiers, is loosely based on Grierson, from a book by Harold Sinclair.