After receiving a colonel's commission from Governor Oliver P. Morton, Reynolds was placed in command of Indiana's Camp Morton, the wartime state's militia muster encampment at Indianapolis. Reynolds's 10th Indiana Volunteer regiment was sent to western Virginia, where it played a decisive role repulsing Confederates under Robert E. Lee at Cheat Mountain.

Although promoted to brigadier general, Reynolds resigned in January 1862 and resumed training Indiana regiments at Camp Morton until November 1862 without a commission. Retroactively appointed colonel of the 75th Indiana volunteers, brigadier general with orders to build a depot and field works in Carthage, Tennessee, and then major general of U.S. volunteers, Reynolds commanded a division of XIV Corps, Army of the Cumberland, at Hoover's Gap and Chickamauga.

After serving as the army's chief of staff before Chattanooga, Reynolds was transferred to the Gulf of Mexico, where he led a division of XIX Corps that garrisoned New Orleans, Louisiana. He was later promoted to the command of the XIX Corps, and then commanded VII Corps in Arkansas.

He was the brother-in law of Brevet Brigadier General Jules C. Webber.