[1] Initially equipped with smoothbore muskets which had been converted from flintlock to percussion, the regiment was then re-equipped with Enfield rifles in May 1862.

[2] On September 17, 1862, at Antietam, the 48th Pennsylvania's brigade assisted in carrying Burnside's Bridge, and crossed it soon after 1:00 PM.

[2] The 48th Pennsylvania served at Falmouth, Virginia, until February 19, 1863, then moved to Newport News, and on to Covington, Kentucky, March 26–April 1.

Seeing heavy action in the Overland Campaign, the regiment participated in the Battles of the Wilderness (May 5–7), Spotsylvania Court House (May 8–12), Stannard's Mills (May 21), North Anna (May 23–26), Line of the Pamunkey, (May 26–28), Totopotomoy Creek (May 28–31), Cold Harbor (June 1–12), and Bethesda Church (June 1–3).

In mid-1864, Grant wanted to defeat Lee's army at Petersburg without resorting to a lengthy siege—his experience in the Siege of Vicksburg told him that such affairs were expensive and difficult on the morale of his men.

Lieutenant Colonel Henry Pleasants, commanding the 48th Pennsylvania Infantry of Major General Ambrose Burnside's IX Corps, offered a novel proposal to solve Grant's problem.

Pleasants, a mining engineer from Pennsylvania in civilian life, proposed digging a long mine shaft underneath the Confederate lines and planting explosive charges directly underneath a fort (Elliott's Salient) in the middle of the Confederate First Corps line.

Digging began in late June, creating a mine in a "T" shape with an approach shaft 511 feet (156 m) long.

The 48th Pennsylvania participated in several further battles of the Petersburg campaign in 1864: Globe Tavern (August 18–21), Peebles's Farm (September 29–October 2), and Boydton Plank Road (October 27–28).

[2] At the Third Battle of Petersburg on April 2, 1865, regimental Surgeon William R. D. Blackwood removed wounded comrades from the battlefield under heavy fire, for which he was later awarded the Medal of Honor.