Meade was serving on survey duty of the Great Lakes when the Civil War broke out. On August 31, 1861, he was appointed Brigadier General of Volunteers and given command of the second brigade of Pennsylvania troops just then organized. He spent that Fall, and the winter of 61/62 working on the Defenses of Washington. On June 18th he was promoted to Major in the Regular Army and joined McClellan in the peninsula commanding the 2nd Brigade, 3rd Division, 5th Corps, Army of the Potomac (A.O.P.). He fought at Mechanicsville, Gaines Mills, and Glendale. On June 30th he was severely wounded in two places and went on sick leave. Partially recovered, he returned to command the 1st Brigade, 3rd Division, Army of Virginia on August 26th. On September 12th he was transferred to command the 3rd Division of the 1st Corps, which he led at South Mountain and Antietam and eventually at Fredericksburg. On November 29th he was promoted to Major General of Volunteers, and on December 25th he was given command of the 5th Corps which he led at Chancellorsville. On June 28, 1863, Meade was given command of the A.O.P. After the Battle of Gettysburg, he was promoted to Brigadier general in the Regular Army for his actions and given the Thanks of Congress. In the next six months the A.O.P. participated in only two indecisive campaigns: Bristoe Station and Mine Run. In the following Spring (1864), U.S. Grant elected to make his headquarters with the A.O.P. From this time until Lee’s surrender at Appomattox Court House, Meade was Grant’s subordinate, although nominally in command of the A.O.P.

He fought at Wilderness, Spotsylvania, Cold Harbor and Petersburg. On August 18, 1864, he was promoted to the rank of Major General in the Regular Army.

At the end of the war, Grant said that Meade “was the right man in the right place” and would “defy any man to name a commander who could’ve done more than Meade did with the same chances”.

Meade was mustered out of the Volunteer Service, but he continued in the Regular Army.