In September 1861, Wheeler was appointed Colonel of the 19th Alabama Infantry. In April 1862, he led a brigade into Battle at Pittsburg Landing. In July, he received command of the cavalry in the Army of Mississippi. In August, he led the advance into Kentucky, during which he participated in the Battle of Perryville. Subsequently, he was promoted to brigadier general as early as October 1862. At the Battle of Stone's River, he earned his next promotion - major general. In September 1863, he participated in the Battle of Chickamauga, and, then he undertook a cavalry raid to the Union rear. In November, he cooperated in the siege of Knoxville, and he was later involved in the rearguard action at Ringgold, November 27, 1863. In 1864, he was active in opposition to General Sherman's advance toward Atlanta. Wheeler fell back slowly in advance of him. In February 1865, he was promoted to Lieutenant General. He fought under General Joseph E. Johnston against Sherman in the Carolinas and, after Johnston's surrender, was captured near Atlanta.